The Astbury Centre for Structural

ASTBURY CENTRE UNDERSTANDING LIFE IN MOLECULAR DETAIL THE ASTBURY CENTRE

CONTENTS

Welcome to the Astbury Centre 03

RESEARCH THEMES 04 RESEARCH CAPABILITIES Chemical Biology 08 Structural Biology 10 Biophysics 12 Molecular Interactions in Cells 14 WELCOME TO THE INDUSTRY PARTNERSHIPS 16 FACILITIES 18 ASTBURY CENTRE PhD TRAINING 20 LIFE IN THE ASTBURY CENTRE 21 Welcome to the Astbury Centre for Structural Molecular The Astbury Centre’s pre-eminence Biology. Our Centre was formally constituted in 1999 in Structural Molecular Biology could STAFF PROFILES 22 and uses the latest tools available to understand life unlock the secrets of mankind’s in molecular detail. We hope that you will find much HISTORY 26 of interest in this brochure that describes the full range deadliest diseases. of the Centre’s activities. Our centre today is a lively, buoyant and invigorating CONTACT US 26 The Astbury Centre brings together around 70 academic research arena that allows new research discoveries to be staff and 400 researchers (including PhD students, made. The aims of the Centre are to research mechanisms ASTBURY REPORTS 27 post-doctoral scientists and research fellows) from , that underpin health and disease and to develop new tools, the biological and medical sciences and chemistry to facilitate methods and technologies. interdisciplinary approaches to unravel life’s mechanisms. These aims are focussed on distinctive strengths in the The Centre has outstanding expertise and research Centre: the dynamic interactome; communication at the infrastructure with all the major techniques required to carry cell membrane; enabling tools for biological and medical out world-class structural molecular and cellular biology discovery healthcare and host-pathogen interactions. research. Our members address major questions associated with biological mechanisms in areas as diverse as chemical Professor Sheena Radford FMedSci, FRS biology, structural biology, biophysics and molecular Director of the Astbury Centre interactions in cells.

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Our research themes address major impact-oriented challenges by drawing on the full breadth of our interdisciplinary capabilities. In each theme, there is a buoyant portfolio of research involving large numbers of PIs within the Centre that RESEARCH additionally draws on our partnerships with academic, clinical and industrial collaborators. The themes are part of broader remit of Astbury Centre which is to harness interdisciplinary THEMES approaches to understand life in molecular detail.

The dynamic interactome Key areas of focus: Enabling tools for biological discovery Key areas of focus: Mission: To understand molecular mechanisms • Intrinsically disordered and intrinsically Mission: To facilitate the development and • Integration of machine learning and technologies to enable across spatial and temporal scales and to uncover disordered regions; application of cutting-edge tools, often inspired discovery of manufacturable biopharmaceuticals; new opportunities for intervention. • -protein interactions and their regulation by by the physical sciences, to enable researchers • “Seeing into Cells” using chemical, biophysical and post-translational modification; to tackle current challenges in biology and bioanalytical approaches to study the mechanism and This theme focuses on understanding and manipulating • The life cycle of proteins; medicine. function of proteins and other macromolecules in cells. biological processes over different time scales, and • Cell signalling networks and interactomes. determining how these molecular mechanisms relate to life. This theme encompasses method- and tool-driven science, Key discoveries made: Approaches exploited include: structural biology, disruptive such as chemical and physical approaches for understanding • Chemical photocrosslinkers for rapid mapping of protein molecular discovery, molecular dynamics, super resolution Key discoveries made: and manipulating biological processes. Our goals are to interactions • Integrated chemical tools and microfluidic technology imaging, chemical tools, single molecule biophysics, develop approaches to drive step-changes in our ability to to map dynamic interactions • Chemical “prosthetics” for restoring protein function biomolecular mass-spectrometry, -omics and cutting edge interrogate biological mechanisms and to facilitate future • Affimers as renewable affinity reagents for studying spectroscopies. • Characterization of functional states of the β-barrel hypothesis-driven life-science research. This includes both biological mechanisms assembly machinery the application and innovative combination of current state-of- Our goals are to drive a step-change in • Understanding of the functional regulation of Aurora the-art tools and the invention and refinement of new tools. • Functionalised quantum dot probes of multivalent protein- ligand interactions our understanding of biological molecular A kinase by protein-protein interactions • A platform for the discovery of diverse functional small • Structural mapping of oligomeric intermediates in amyloid Some approaches currently being developed are: platforms mechanisms via: molecules with novel functions. assembly pathways to discover next-generation small molecule tools, surface • application and innovative combination of state-of-the-art mimics of biological interfaces, advanced microfluidic devices, tools to study biomacromolecule folding, aggregation and • Characterization of allosteric regulation in soft matter tools for biology, computational methods and the interactions in a systems and cellular context mechanosensitive ion channels. development of analytical tools (such as single-molecule • development of methods to manipulate and understand spectroscopy, combined microscopies and structural mass dynamic biomolecular mechanisms. spectrometry).

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Communication at cell membranes Host-Pathogen interactions Key areas of focus: Key areas of focus: Mission: To understand how interactions at cell Mission: To understand the molecular biology • Understanding how signalling at the cell membrane can • Understanding virus lifecycles from infection to release membranes result in cellular responses in health result in disease states of viruses and bacteria that cause disease in using high-resolution structural and imaging approaches. and disease. • Understanding the role of the glycocalyx in transport and , and plants, and to translate • Leveraging expertise in chemical biology to interrogate signalling across membranes these findings into new tools for prevention, infection and develop novel strategies for anti-infectives. Cell membranes are the centres of communication between • Development of new scaffolds to generate more native-like detection and eradication of these pathogens. the inside and outside cellular worlds. We are working across environments for membrane proteins Key discoveries made: disciplinary boundaries to understand, at the molecular scale, Viruses and bacteria are the cause of significant disease the mechanisms that regulate the reception of signals, their • The single-stranded RNA genomes of many viral Key discoveries made: in humans, animals and plants. For example, bacteria are pathogens are a “self-instruction manual” for the integration and processing, and the formulation of a response. developing resistance to current antibiotics, threatening • Detergent-free isolation of membrane proteins in their lipid production of the infectious virions This is a formidable challenge, but it will provide novel our ability to treat common infectious diseases, resulting environment • Bunyaviruses require cellular potassium to infect cells, opportunities to enhance our understanding of fundamental in prolonged illness, disability, and death. Viral infections a finding that we are harnessing to repurpose clinically- biological processes. Moreover, it will aid in the development • Understanding how extracellular matrix can discriminate are also a cause of global mortality and morbidity, with approved drugs to treat these viral infections of bioactive surfaces, scaffolds and delivery vehicles to cells by their receptor density, and how this pandemic virus being the most significant disease control and sense cellular fate for applications in regenerative ‘superselectivity’ can improve targeting of cells in risk in the UK, according to the National Risk Register of • Activation of an IL-6 signalling axis drives autocrine STAT3 medicine, targeted drug delivery and diagnostics. biomedical applications. Civil Emergencies (e.g. COVID-19). To reduce the risks of activation, providing an opportunity to use clinically • Re-engineering of peroxisome import pathways to deliver these and other infections, our research uses molecular and approved drugs to treat HPV-mediated cervical cancer cargo to different cellular compartments. cellular techniques, combined with structural and chemical • Oncogenic herpesvirus Kaposi’s sarcoma-associated • Understanding multivalent lectin-carbohydrate recognition approaches, to understand in molecular detail how these herpesvirus (KSHV) sequesters a host cell complex, using functionalised quantum dots. pathogens grow, cause disease and evade treatment. We hTREX, to enhance viral mRNA processing and replication, harness our knowledge of these fundamental processes a finding that has allowed us to inhibit KSHV replication to devise new approaches to prevent and treat infectious • Computational drug design has yielded β-lactamase disease. inhibitors which circumvent evolved resistance to many current antibiotics.

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CHEMICAL BIOLOGY

Chemical Biology is the application of chemical tools and We have superb facilities for Chemical Biology including approaches to address biological problems. Within the Astbury integrated synthetic and biological laboratories, a computer Centre, chemists are engaged in highly interdisciplinary and cluster dedicated to ligand design, a facility for screening collaborative research programmes to address a wide range compound libraries for biological function and a suite dedicated of biological, chemical and medical problems. to the high-throughput synthesis of small molecules.

These include the design and synthesis of new drugs, We exploit these facilities, in conjunction with biophysical, the development and exploitation of small molecule tools structural and cellular approaches, to address a wide range to interrogate biological mechanisms, pioneering new of problems of direct relevance to society. approaches in synthetic biology and engineering new enzymes for use in synthetic chemistry.

Professor Andrew Wilson is leading an EPSRC programme and structural ensembles (from NMR or molecular dynamics Protein-protein interactions grant in which new tools to drive the discovery of inhibitors data). The approach enabled the accurate prediction of Protein–protein interactions (PPIs) are vital to all of PPIs are being developed. The programme involves hot-spot residues at a wide range of topographically distinct biological processes, and have huge potential as collaboration with researchers from the University of Bristol, protein–protein interfaces. Knowledge of the hot-spot targets for drug discovery. PPIs typically occur over and has three project partners: AstraZeneca, Domainex and residues has enabled the discovery of several different large topographically shallow protein surfaces, and Northern Institute for Cancer Research. classes of PPI modulators: for example, coiled coils can exhibit a broad range of affinities. However, (Chemical Science 2018), oligoamide foldamers (Chemical understanding the key determinants of the Science 2019) and stapled peptides (ChemBioChem 2019). thermodynamic stability of specific PPIs remains The team has undertaken a comparative analysis of multiple a key challenge. methods for the prediction of hot-spot residues on the basis of PPI structures (ACS Chemical Biology 2019). Here, a new method, BUDE Alanine Scanning, was introduced which can be applied to both single structures (from )

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STRUCTURAL BIOLOGY

The Astbury Centre has a strong history in structural resonance spectroscopy (NMR), atomic force microscopy studies from small molecules to large protein complexes. (AFM) and electron microscopy (EM) and this structural Bill Astbury’s definition of the alpha-helix and beta-sheet information is complemented by biophysical techniques structures within proteins laid the foundations for the high such as analytical ultracentrifugation, isothermal titration resolution structural studies of bio-molecules that are calorimetry, circular dichroism spectroscopy (CD), surface carried out in the Centre today. plasmon resonance (SPR), and fluorescence. We take advantage of our excellent modern facilities, along with the Understanding the structure of a protein or protein many cross-disciplinary collaborations within the Centre, to complex is fundamental to underpinning drug design investigate the structural biology of aspects of life sciences and understanding the relationship between structure such as enzyme mechanisms, membrane proteins, and function. The Astbury Centre has a wealth of molecular motors, virus biology, molecular dynamics, expertise in X-ray crystallography, nuclear magnetic and more.

2019) revealed a fascinating molecular mechanism inhibiting enzyme activity. This block is thought to prevent Metabolic control of immune that connected the ubiquitin-processing enzyme BRISC abnormal BRISC activity and restrict it to inflammatory sites signaling revealed by cryo-EM to an enzyme involved in metabolism called serine to keep immune signaling in line. hydroxymethyltransferase 2 (SHMT2). SHMT2 guides The overproduction of cytokines results in hyper-inflammation reactions essential for basic body functions, such as By probing the detailed structure of the complex and that can cause tissue damage and lead to autoimmunity. In many building blocks for proteins and DNA, after being activated in collaboration with cell and clinical biologists from the autoimmune diseases such as Lupus, systemic sclerosis and by a form of vitamin B6. University of Pennsylvania and , the rheumatoid arthritis, immune cells produce too much interferon, team found that SHMT2 is also required for immune cells a natural stimulant that signals to the immune system in ways that The team solved the cryo-EM structure of the human to send out cytokine signals through its interaction with can exacerbate inflammation. BRISC-SHMT2 molecular complex. They found that it is the BRISC complex. Mutations that disrupt the interaction composed of eight BRISC-enzyme protein subunits forming surface of BRISC-SHMT2 complex interfere with this Structural biologists in the Astbury Centre led by Dr Elton Zeqiraj, in a U-shape structure, with different enzyme components onslaught of inflammation. This interaction was also have figured out the structure of a macromolecular complex by protruding from each side. SHMT2 bridges the gap regulated by vitamin B6 levels in cells, providing clues to using cryo-electron microscopy (cryo-EM). Their findings (, between the two arms, blocking the active-site pocket, and the impact of metabolism on immune response regulation.

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BIOPHYSICS

The understanding of life requires a detailed knowledge of nuclear magnetic resonance (NMR) reveal information about the structure of biological macromolecules and how they conformational changes during binding. interact with each other and with other molecules in the living cell. Our researchers exploit the widest possible array of Single molecule methods, including fluorescence resonance biophysical methods to determine the specificity, rates, and energy transfer (FRET) and force spectroscopy are also equilibrium free energies of interactions between proteins, being used to reveal new information about protein stability nucleic acids, lipids, carbohydrates and small molecule and force-induced conformational changes. Combined ligands. Techniques such as microfluidics, surface plasmon with insights from molecular dynamics simulations and resonance (SPR), isothermal titration calorimetry (ITC), mathematical modelling, our aim is to use state-of-the art quartz crystal microbalance (QCM-D) and fluorescence biophysical methods to develop new approaches able to based assays (intensity and anisotropy) are used to elucidate elucidate how macromolecular assembly and recognition is binding constants, whilst structural methods including controlled within cells and tissues to the exquisite sensitivity circular dichroism (CD), ion mobility mass spectrometry, and required for healthy life.

Professor Stephen Evans along with PhD student regime. Further work, looked at the mechanical High throughput mechanical Fern Armistead used a microfluidic technique called properties of three colorectal cancer cell lines as a model deformation cytometry for various studies on the sensitivity for metastatic progression (Scientific Reports, 2020). phenotyping of single cells of cells to subcellular alterations, and mechanical Results showed that cells become softer with cancer The mechanics of a single cell can be an indicator changes with colorectal cancer progression. Here, cells progression. They also showed that multiparameter of diseased state, thus mechanophenotyping offers were deformed at the stagnation point of an extensional analysis is required to accurately characterise the many potential diagnostic applications. A high- flow across a wide range of flow conditions. One study different cell types, including both deformation and throughput method is required for single cell mechanical (Biophysical Journal, 2019) showed that different flow relaxation properties. measurements to account for cell heterogeneity which conditions probe different aspects of the cell structure. arises due to cell-cycle stage and biological noise. For example, changes in actin structure, due to drug Overall, the technique provides a range of mechanical Microfluidics can be used to hydrodynamically deform induced destabilisation, led to cells becoming more parameters for understanding cell behaviour and gives cells in a high-throughput manner, allowing automated deformable and was best observed in a shear-force new insights into heterogeneity, disease progression and single cell analysis. dominant regime. In contrast changes to the nuclear drug response. structure are best observed in an inertial force dominant

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MOLECULAR INTERACTIONS IN CELLS

To complement analyses using biophysical approaches At an individual cell level, conventional light microscopy (e.g. in vitro, researchers in the Astbury Centre also study molecular confocal and deconvolution) studies can be complemented interactions in the context of the whole cell. by super-resolution approaches (PALM/STORM and iSIM). In addition, correlative light-electron microscopy (CLEM) Protein-, protein-protein and protein-lipid allows the integration of datasets derived from different imaging interactions within cells are investigated using biochemical modalities to provide unique insights into the localisation approaches such as immunoprecipitation, purification via of biological molecules within cells. protein tags and the application of proteomic technologies. Finally, a confocal microscope situated in the Category III Within the Astbury Centre these methods are complemented by containment facility provides the opportunity to study cells a range of state-of-the-art bio-imaging equipment to investigate infected with pathogens. the biology of cells at different resolutions. Populations of cells are interrogated by flow cytometry and cell sorting.

the m6A methylation pathway, chemically adds a methyl a new family of proteins, the ‘Royal family’, could The virus with royal protection group to adenosines in messenger RNA (mRNA). Once recognise and bind viral mRNAs that contains the m6A Viruses are the masters of manipulation. Key modified these mRNAs are then recognised by so-called chemical modification. Further experiments showed to their success is the ability to subvert host ‘m6A reader’ proteins which bind the m6A chemically that Royal family members, such as SND1, specifically cell pathways and machinery to enhance viral modified mRNA and then determine what happens to stabilise viral mRNAs once bound to them. Notably, replication and proliferation. Professor Ade that modified mRNA. upon depletion of SND1 from virus infected cells showed Whitehouse’s group have recently identified a that SND1 is essential for KSHV replication. These novel cellular pathway that the human tumour The study firstly identified that KSHV manipulates the findings open up new therapeutic strategies to inhibit the virus, Kaposi’s sarcoma-associated herpesvirus m6A methylate pathway to chemically modify its own viral replication of this important human pathogen. (KSHV), manipulates to enhance its own mRNAs (eLife, 2019). The study then addressed why this replication. This host cell pathway, known as enhances virus replication. Experiments revealed that

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Case study: Biological (protein) drugs have emerged as effective and high-value therapeutics, capable of treating a wide range of medical conditions not possible with small-molecule INDUSTRY drugs. Their large-scale expression, purification and formulation is problematic however, because changes in their environment during processing can lead to their partial unfolding and aggregation which is difficult to predict. Aggregation can lead to a number of problems PARTNERSHIPS including loss of (expensive) drug product, a potential The discovery and manufacture of novel, safe, and The Astbury Centre facilitates translational research immunological response which is damaging to the effective therapeutics remains a difficult and arduous through a range of activities including linkage to national patient, and ultimately the loss of a drug programme task. For example, it has been estimated that bringing initiatives, industry-focussed workshops and networking which a company has invested significant resources and each new drug to market costs over £1bn. Partnerships events, implementation of impact activities, funding of where there is medical need. between academia and industry are an increasingly proof-of-concept projects, and assisting academics to important mechanism to facilitate early-stage drug identify the best route to exploit intellectual property. To address this problem, Dr David Brockwell and discovery through the development of new methods and Professor Sheena Radford from the Astbury Centre, along fundamental science. To remain focussed on sector needs, the Astbury Centre with Professor Nik Kapur (Mechanical Engineering), is guided by an Industrial Advisory Board comprising worked with AstraZeneca and others to develop novel Engagement and collaboration with industry is central representatives from large and small pharmaceutical/ methods to predict and prevent protein aggregation to the Astbury Centre. The Centre works with a wide biotechnology companies and allied industries. The in vitro using hydrodynamic flow (Proceedings of the range of industrial partners to drive innovation in the Centre’s Research and Innovation Development Manager National Academy of Sciences of the USA, 2017) and pharmaceutical and biotechnology industries, and also also works closely with related innovation professionals in vivo. In the latter method, aggregation is linked to the supports researchers to commercialise their research. across the university (including health and life sciences, antibiotic resistance of E. coli, allowing high through-put Reflecting areas of research strength within the Astbury and physical sciences) to deliver coordinated support for screening and re-engineering of problematic sequences Centre which align with industrial needs, we focus on: pharmaceutical research at Leeds. by directed evolution (Nature Communications, 2020).

• predicting and preventing protein aggregation; The Astbury Centre and the University of Leeds are “Working with AstraZeneca has been a brilliant and • modulating protein-protein interactions; also formal partners of the Institute, inspiring experience. This is a true collaboration • targeted molecular delivery; further strengthening our industrial engagement between academics and industry and is reaping real • ion channel research; and partnership. benefits to all involved.” • translational drug discovery; More information can be found at: Professor Sheena Radford, Astbury Professor of Biophysics, University of Leeds Alongside these themes, platform technologies to http://pharmahub.leeds.ac.uk facilitate therapeutics discovery are also supported.

The Astbury Centre has a strong track record of industry engagement and their expertise has delivered value to our R&D.

Principal Scientist, Medicinal Chemistry, AstraZeneca

16 www.astbury.leeds.ac.uk www.astbury.leeds.ac.uk 17 FACILITIES THE ASTBURY CENTRE FACILITIES An abundance of instrumentation that includes both EPSRC, MRC and the Wellcome Trust. Access to cutting- well-established and emerging techniques lies at the edge instrumentation is core to the Centre’s success heart of the Astbury Centre’s research successes. Each is and this importance is underlined by the creation of the run by dedicated and highly experienced staff scientists Astbury Biostructure Laboratory in 2016 – a £17 million and facility managers who offer training to all users. This investment by the University of Leeds and the Wellcome infrastructure is maintained at the cutting-edge by funding Trust to provide two Titan Krios cyro-electron microscopes from a diverse range of agencies including charities, and a 950 MHz NMR and associated staff scientists. private benefactors, the University of Leeds, BBSRC,

Electron Microscopy X-ray crystallography Advanced NMR Single Particle Cryo-EM, Automatic dropsetter Structural dynamics, Tomography, Cellular EM and imaging, FBDD BRUKER 950 MHz, Cryoprobes

Understanding peptide The mechanisms of Aβ peptide neurotoxicity in Alzheimer’s assembly mechanisms disease are hotly debated. One suggested mechanism is that the peptides assemble in membranes to form β-barrel shaped Cell biology Molecular interactions Protein Production Understanding the structural mechanism by which proteins oligomeric pores that induce cell leakage. Direct detection of Bioimaging, Super-resolution ITC, AUC, DSC, SPR, OPTIM Bacterial, insect and mammalian and peptides aggregate is crucial, given the role of fibrillar such putative assemblies and their exact oligomeric states Microscopy, Flow Cytometry SEC-MALLS, Thermophoresis expression,High-Throughput large scale Cloningpurification aggregates in debilitating amyloid diseases and bioinspired is however complicated by a high level of heterogeneity. By FPLC systems, Fermentors materials. Yet, this is a major challenge as the assembly employing a native mass spectrometry approach Professor involves multiple heterogeneous and transient intermediates. Frank Sobott and his collaborators have used native ESI-IM- Teams of chemists and structural biologists in the Astbury MS to watch the assembly of Aβ42 with membrane mimetic Centre are engaged in multidisciplinary programmes of detergent micelles, exploiting the powers of native MS methods research to understand peptide and protein assembly to unpick this molecular complexity. The study revealed mechanisms and to determine how we can intervene in these the formation of hexamers with collision cross sections in assembly processes. agreement with a β-barrel structure (Journal of the American Chemical Society, 2019). The results support the oligomeric Analytical methods Mass Spectrometry Advanced Robotics In work performed with Professors Sheena Radford and HPLC, CD Spectroscopy, Non-Covalent Interactions, High-Throughput Screening, pore hypothesis as one important cell toxicity mechanism Fluorescence Spectroscopy Chemical Proteomics Bioscreening Technology Andrew Wilson, Sam Bunce, a BBSRC DTP funded PhD in Alzheimer’s disease and highlight the power of native student, analysed the co-aggregation of Aβ40 and Aβ16–22, mass spectrometry as an approach to search for methods to

two widely studied peptide fragments of Aβ42 implicated in stabilise or destabilise the molecules by molecules of cellular or Alzheimer’s disease. Using fluorescence assays, electrospray therapeutic relevance. ionisation MS coupled with ion mobility MS (ESI–IMS–MS), photoinduced cross-linking experiments, and molecular

dynamics simulations, they demonstrated that Aβ16–22

increases the aggregation rate of Aβ40 through a surface- catalysed secondary nucleation mechanism, paving the way Bioscreening Single Molecule Methods Surface Analysis to the generation of surfaces able to enhance or suppress Affimer technology for specific, Single Molecule Fluorescence, AFM, XPS, QCMD aggregation. The work provides the first molecular images high affinity probes Single Molecule Force Methods of amyloid secondary nucleation that they are now using to inform effective design of ligands that modulate therapeutically For further details please see www.astbury.leeds.ac.uk/research/facilities.php important amyloid assembly (Science Advances, 2019).

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PhD LIFE IN THE TRAINING ASTBURY CENTRE Overview The Astbury Society The Astbury Centre plays a major role in training highly Our programmes investigate the molecular basis of The Astbury Society, comprised of PhD students and motivated researchers to become skilled in interdisciplinary biological mechanisms, and the strategic applications postdoctoral members, plays a key role in encouraging life sciences. Funding for PhD training is provided from a of mechanistic biology. We train students in the wide cross-departmental collaborations by organising social wide variety of sources including the White Rose BBSRC range of techniques in cell biology, biological chemistry, events including an Annual Sports Day, the May Ball, Doctoral Training Programme (with York and Sheffield), structural biology and biophysics that are needed to team working events and seminars with guest speakers. BBSRC iCASE studentships in collaboration with industry answer key questions in challenge-led including food The events of the Astbury Society are enjoyed by partners, EPSRC and the MRC Discovery Medicine North security, bioenergy and industrial biotechnology and postgraduate students, postdoctoral researchers and (DiMeN) DTP (with Sheffield, Newcastle and Liverpool). the development of new tools and techniques focussed academic staff alike. PhD students are also funded by bio-medical charities on key questions and challenges in in bioscience and including The Wellcome Trust, the British Heart Foundation, biomedicine. Our programmes range from 3½ to 4 years Kidney Research UK, Cancer Research UK and Alzheimer’s duration and may include laboratory rotations to train Research UK. students in specific techniques or as ‘taster’ sessions Meeting various people from different before a main PhD project is chosen. academic departments in a social The diversity of our science and the Centre members is environment allows for time to discuss also reflected in the wide range of academic disciplines The PhD training in The Astbury Centre includes aspects of my PhD and to get a range of and nationalities of the students that are studying with bespoke cohort-wide training in core skills such as ideas that might have not been brought us. Our cohort of >200 PhD students includes physicists new technologies allowing students to develop a deep chemists, biologists and students with a wide range of other understanding of modern techniques, their principles and to my attention otherwise. undergraduate disciplines, working together from countries applications, mathematics, data-analysis and modelling. spanning the UK, Europe, USA, Canada, Australia, China, These generic skills are supplemented with practical Paul Devine, PhD student Mexico,the Middle East and India. training and skills modules in techniques specifically related to their PhD project. Our programmes encourage Our PhD students work in an academically stimulating interdisciplinarity and provide a wide generic skills base to Being part of the Astbury Society has environment, which is supportive, collegiate and inclusive. provide the foundation of a wide range of future careers. certainly had a positive impact on All students have a small supervisory team to oversee Some programmes also include a 3 month ‘Professional my PhD, predominantly due to the and facilitate progress and to help promote our ethos of Internship for PhD Students’ (PIPS) gaining experience of interdisciplinary nature of the Centre. multidisciplinary training. Students form an integrated work in a professional environment and transferable skills. cohort within the Centre through training days and other There are always people, from a range activities such as the Annual Research Retreat which all of scientific backgrounds, who will students are invited to attend. happily let you bounce ideas off them to help you along with your PhD. Claire Windle, PhD student

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Dr Simon Connell Dr Kevin Critchley Dr Lorna Dougan Dr Thomas Edwards Prof Steve Evans Associate Professor Associate Professor Professor of Physics Associate Professor Professor of Molecular [email protected] [email protected] [email protected] [email protected] and Nanoscale Physics Keywords: AFM, lipid Keywords: quantum dots; Keywords: physics of Keywords: [email protected] membranes; fibrin nanoparticles; bioimaging life; extreme conditions RNA binding proteins Keywords: lipid membranes; STAFF & structural biology microbubbles; nanomaterials

Dr Peter Adams Prof Alison Baker Dr John Barr Prof Richard Bayliss Prof Colin Fishwick Dr Juan Fontana Dr Richard Foster Dr René Frank Dr Stephen Griffin University Academic Fellow Professor of Plant cell Associate Professor Professor of Molecular Professor of Medicinal University Academic Associate Professor University Academic Fellow Associate Professor Chemistry [email protected] and Molecular Biology [email protected] Medicine Fellow [email protected] [email protected] [email protected] [email protected] Keywords: bionanophysics, [email protected] Keywords: RNA virus [email protected] [email protected] Keywords: medicinal Keywords: Cryogenic Keywords: viroporins; lipid membranes, photosynthesis Keywords: peroxisomes, protein nucleocapsid structure Keywords: Structural Keywords: medicinal Keywords: Virus structure, chemistry; virtual drug design correlated light-electron hepatitis C virus trafficking, ABC transporters biology, protein kinases, chemistry; computational electron microscopy, Herpes microscopy; Cryo-electron cancer, drug discovery molecular design Simplex Virus, Influenza tomography; Mouse genetics; Structural neuroscience

Dr Paul Beales Dr Yoselin Benitez Alfonso Prof Alan Berry Dr Robin Bon Prof Adrian Goldman Dr Yuan Guo Prof Mark Harris Dr Sarah Harris Dr George Heath Associate Professor Lecturer in Plant sciences Professor of Associate Professor Leadership Chair in Lecturer in Food Science Professor of Virology Lecturer in University Academic Fellow [email protected] [email protected] Molecular Enzymology [email protected] Membrane Biology & Nutrition [email protected] Biological Physics [email protected] Keywords: lipid Keywords: Cell-to-cell [email protected] Keywords: calcium [email protected] [email protected] Keywords: hepatitis [email protected] Keywords: High-Speed membranes; nanomedicine communication, Plasmodesmata, Keywords: protein channel inhibitors; Keywords: structural studies Keywords: Multivalent lectin- C virus; RNA protein Keywords: computational Atomic Force Microscopy; Plant development, Cell wall engineering; directed contrast agents of membrane-systems carbohydrate recognition, signalling interactions biophysics; MD Membrane Proteins; Lipid biopolymers evolution; enzymology and endocytosis, immune Membranes; Biophysics regulation, allergy and cancer

Dr Joe Cockburn Prof Alex Breeze Dr David Brockwell Dr Anton Calabrese Dr Glyn Hemsworth Prof Peter Henderson Dr Morgan Herod Dr Eric Hewitt Dr Lars Jeuken Lecturer in X-ray BBSRC David Phillips Professor of Biomolecular NMR Associate Professor University Academic Fellow Professor of Biochemistry MRC CDA Fellow and Senior Lecturer in Cell Professor of Molecular Crystallography Fellow and University and Molecular Biology University Academic Fellow Biophysics [email protected] [email protected] [email protected] Academic Fellow Biology and Immunology [email protected] [email protected] [email protected] Keywords: nuclear magnetic Keywords: protein; folding; Keywords: Mass [email protected] [email protected] [email protected] unfolding; force; AFM Keywords: structural resonance; structural and spectrometry, Structural Keywords: structural Keywords: membrane Keywords: Virus Replication, Keywords: cell biology; Keywords: bioinorganic biology of the cytoskeleton chemical biology; Proteomics, Biomolecular biology; enzymes; transport; antibiotic Assembly/Disassembly, immunology; amyloid chemistry; membrane protein-protein interactions analysis, Protein glycobiology; biotechnology resistance Virus-Host Interactions, disease biology conformational dynamics Polyprotein Processing 22 www.astbury.leeds.ac.uk www.astbury.leeds.ac.uk 23 INDUSTRYSTAFF PROFILES FOCUS THE ASTBURY CENTRE

Dr Sergei Krivov Prof John Ladbury Dr Andrew Macdonald Dr Antreas Kalli Dr Jamel Mankouri Prof Peter Stockley Prof Nicola Stonehouse Prof Paul Taylor Dr Chris Thomas Dr Neil Thomson RCUK Academic Professor of Associate Professor University Academic Fellow Royal Society University Professor of Biological Professor in Molecular Professor of Chemical Lecturer Reader in Biological Physics Research Fellow Mechanistic Biology [email protected] [email protected] Research Fellow Chemistry Virology Education [email protected] and Bionanotechnology [email protected] [email protected] Keywords: virus; chronic Keywords: membrane [email protected] [email protected] [email protected] [email protected] Keywords: plasmid; [email protected] Keywords: Keywords: structure/function; disease; host interactions proteins, lipid membranes, Keywords: virus pathogenesis; Keywords: virus Keywords: virus; vaccines; Keywords: chemical replication; Keywords: protein folding; protein signalling; drug molecular modelling ion channels assembly; aptamers & aptamers genomics, drug re-profiling, mobilisation; relaxase bionanotechnology; computational biology discovery; cellular mechanisms bionanotechnology cancer treatments DNA-protein interactions

Dr Darren Tomlinson Dr Roman Tuma Dr Andrew Tuplin Dr Bruce Turnbull Dr Stuart Warriner Dr Kenneth McDowall Dr Stephen Muench Prof Adam Nelson Dr Takashi Ochi Dr Alex O’Neill Associate Professor and Reader in Lecturer Professor of Senior Lecturer Associate Professor in Associate Professor Professor of Chemical Biology University Academic Fellow Associate Professor Molecular Microbiology University Academic Fellow Biophsyics [email protected] Biomolecular Chemistry s.l.warriner@ [email protected] [email protected] [email protected] [email protected] [email protected] d.c.tomlinson@ [email protected] Keywords: virus; [email protected] chem.leeds.ac.uk Keywords: Structural Keywords: chemical biology; Keywords: Centrosome, Keywords: bacteriology; leeds.ac.uk Keywords: virus; virology; Keywords: chemical Keywords: Keywords: microbial; gene biology; V-ATPase; rational diversity-oriented synthesis Cilia, Structural protein, antibacterials; resistance regulation; RNA turnover drug design Structure biology Keywords: artificial binding single molecule RNA structure; glycobiology; protein chemical biology; proteins; protein interactions biophysics; helicase replication interactions organic synthesis

Dr Patricija Van Oosten-Hawle Lecturer in Molecular Dr Emanuele Paci Prof Michelle Peckham Dr Christos Pliotas Prof Sheena Radford Dr Michael Webb Prof Adrian Whitehouse Prof Andy Wilson Dr Megan Wright Dr Stephanie Wright and Cell Biology Associate Professor Professor of Cell Biology Lecturer in Integrative Astbury Professor Associate Professor Professor in Molecular Professor of Organic University Academic Fellow Senior Lecturer in Membrane Biology of Biophysics Virology Chemistry Biochemistry and p.vanoosten-hawle@ [email protected] [email protected] in Chemistry [email protected] [email protected] [email protected] [email protected] [email protected] Molecular Biology leeds.ac.uk Keywords: biological Keywords: myosins; [email protected] Keywords: chemical biology, [email protected] Keywords: proteostasis; physics; statistical structure; imaging; Keywords: Mechanosensation; Keywords: protein folding; Keywords: enzymology; Keywords: viruses; Keywords: chemical proteomics, chemical probe, transcellular stress signalling; mechanics muscle PELDOR/DEER spectroscopy; protein aggregation; amyloid bio organic chemistry cancer; KSHV; MCPyV biology; protein-protein protein labelling Keywords: cancer biology; protein conformational Ion channels; EPR interactions eukaryotic gene regulation diseases; C. elegans

The staff list is up to date as of day of printing but is subject to change. Please check the Astbury Centre website for up to date information Prof Neil Ranson Dr Ralf Richter Prof David Rowlands Prof Frank Sobott Dr Qian Wu Dr Elton Zeqiraj Prof Dejian Zhou Dr Anastasia Zhuravleva www.astbury.leeds.ac.uk/ Professor of Structural Associate Professor Emeritus Professor of Dr Ryan Seipke Professor of Biomolecular University Academic Fellow Sir Henry Dale and Professor of Senior Lecturer Lecturer in Bacteriology people/people.php Molecular Biology [email protected] Virology Mass Spectrometry [email protected] University Academic Fellow Nanochemistry [email protected] [email protected] [email protected] Keywords: physical [email protected] [email protected] Keywords: DNA repair, [email protected] [email protected] Keywords: molecular drug Keywords: electron chemistry of biological Keywords: RNA viruses; Keywords: Keywords: ion mobility DNA damage response, Keywords: Ubiquitin, Keywords: nanoparticle; chaperones; stress microscopy; systems; bottom-up replication; structure; discovery; synthetic spectrometry, structural structural biology, pathway Cell signalling, DUBs biosensing; response; NMR macromolecular assembly synthetic biology vaccines biology; gene regulation proteomics, biomolecular choice nanomedicine analysis 24 www.astbury.leeds.ac.uk www.astbury.leeds.ac.uk 25 HISTORY THE ASTBURY CENTRE HISTORY ASTBURY REPORTS

The Astbury Centre for Structural Molecular Biology was We are at the dawn of a new era, the era The research undertaken by Astbury Centre investigators is described in greater detail in our annual reports. formally constituted as a University Interdisciplinary Research of ‘molecular biology’ as I like to call it, These accounts, first published in 2000, are available online: www.astbury.leeds.ac.uk/research/reports.php Centre in 1999. The Centre builds on the visions and and there is an urgency about the need achievements of the pioneers of modern biophysics and is named after W.T. (Bill) Astbury FRS, a biophysicist who laid for more intensive application of physics many of the foundations of the field during a long research and chemistry, and specially of structure Astbury Report 2018 career at the University of Leeds (1928-1961). Astbury analysis, that is still not sufficiently Astbury Report 2019 originally identified the two major recurring patterns of protein appreciated. structure (alpha and beta), took the first X-ray fibre diffraction pictures of DNA (in 1938) and is widely credited with the Bill Astbury 1947 definition of the field of molecular biology. Astbury’s work, The Astbury Centre for The Astbury Centre for in turn, followed on from the pioneering work of Sir William Structural Molecular Biology Structural Molecular Biology Bragg who was the Cavendish Professor of Physics in Leeds from 1908-1915. ANNUAL ANNUAL REPORT 2018 REPORT 2019 Contact us General enquiries should be addressed to the Centre’s Administrative team:

Astbury Centre for Structural Molecular Biology University of Leeds, Leeds, LS2 9JT Email: [email protected] www.astbury.leeds.ac.uk

The Astbury Centre for The Astbury Centre for Structural Molecular Biology Structural Molecular Biology University of Leeds University of Leeds Leeds University of Leeds Leeds University of Leeds LS2 9JT Leeds, LS2 9JT Leeds, United Kingdom Tel: 0113 343 3086 LS2 9JT Tel: 0113 343 3086 LS2 9JT [email protected] Tel: 0113 243 1751 [email protected] Tel: 0113 243 1751 www.astbury.leeds.ac.uk www.leeds.ac.uk www.astbury.leeds.ac.uk www.leeds.ac.uk

26 www.astbury.leeds.ac.uk www.astbury.leeds.ac.uk 27 We need much more cooperation, much more fraternization, much more encouragement of one another, much more sharing of knowledge and much more asking of help.”

WILLIAM ASTBURY, PROFESSOR OF , 1948

The Astbury Centre for Structural Molecular Biology University of Leeds Leeds, United Kingdom LS2 9JT

Tel. +44 (0)113 343 3086 [email protected] www.astbury.leeds.ac.uk www.astbury.leeds.ac.uk