On the Binding Affinity of Macromolecular Interactions: Daring to Ask Why Proteins Interact Rsif.Royalsocietypublishing.Org Panagiotis L
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Selective and Specific Ion Binding on Proteins at Physiologically-Relevant
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector FEBS Letters 585 (2011) 3126–3132 journal homepage: www.FEBSLetters.org Selective and specific ion binding on proteins at physiologically-relevant concentrations ⇑ Linlin Miao a, Haina Qin a, Patrice Koehl a,b, Jianxing Song a,c, a Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore b Department of Computer Science and Genome Center, University of California, Davis, CA 95616, USA c Department of Biochemistry, Yong Loo Lin School of Medicine and National University of Singapore, 10 Kent Ridge Crescent, Singapore 119260, Singapore article info abstract Article history: Insoluble proteins dissolved in unsalted water appear to have no well-folded tertiary structures. Received 30 July 2011 This raises a fundamental question as to whether being unstructured is due to the absence of salt Revised 25 August 2011 ions. To address this issue, we solubilized the insoluble ephrin-B2 cytoplasmic domain in unsalted Accepted 29 August 2011 water and first confirmed using NMR spectroscopy that it is only partially folded. Using NMR HSQC Available online 6 September 2011 titrations with 14 different salts, we further demonstrate that the addition of salt triggers no signif- Edited by Miguel De la Rosa icant folding of the protein within physiologically relevant ion concentrations. We reveal however that their 8 anions bind to the ephrin-B2 protein with high affinity and specificity at biologically-rel- evant concentrations. Interestingly, the binding is found to be both salt- and residue-specific. Keywords: Insoluble protein Ó 2011 Federation of European Biochemical Societies. -
Hypochlorous Acid Handling
Hypochlorous Acid Handling 1 Identification of Petitioned Substance 2 Chemical Names: Hypochlorous acid, CAS Numbers: 7790-92-3 3 hypochloric(I) acid, chloranol, 4 hydroxidochlorine 10 Other Codes: European Community 11 Number-22757, IUPAC-Hypochlorous acid 5 Other Name: Hydrogen hypochlorite, 6 Chlorine hydroxide List other codes: PubChem CID 24341 7 Trade Names: Bleach, Sodium hypochlorite, InChI Key: QWPPOHNGKGFGJK- 8 Calcium hypochlorite, Sterilox, hypochlorite, UHFFFAOYSA-N 9 NVC-10 UNII: 712K4CDC10 12 Summary of Petitioned Use 13 A petition has been received from a stakeholder requesting that hypochlorous acid (also referred 14 to as electrolyzed water (EW)) be added to the list of synthetic substances allowed for use in 15 organic production and handling (7 CFR §§ 205.600-606). Specifically, the petition concerns the 16 formation of hypochlorous acid at the anode of an electrolysis apparatus designed for its 17 production from a brine solution. This active ingredient is aqueous hypochlorous acid which acts 18 as an oxidizing agent. The petitioner plans use hypochlorous acid as a sanitizer and antimicrobial 19 agent for the production and handling of organic products. The petition also requests to resolve a 20 difference in interpretation of allowed substances for chlorine materials on the National List of 21 Allowed and Prohibited Substances that contain the active ingredient hypochlorous acid (NOP- 22 PM 14-3 Electrolyzed water). 23 The NOP has issued NOP 5026 “Guidance, the use of Chlorine Materials in Organic Production 24 and Handling.” This guidance document clarifies the use of chlorine materials in organic 25 production and handling to align the National List with the November, 1995 NOSB 26 recommendation on chlorine materials which read: 27 “Allowed for disinfecting and sanitizing food contact surfaces. -
Peptide Chemistry up to Its Present State
Appendix In this Appendix biographical sketches are compiled of many scientists who have made notable contributions to the development of peptide chemistry up to its present state. We have tried to consider names mainly connected with important events during the earlier periods of peptide history, but could not include all authors mentioned in the text of this book. This is particularly true for the more recent decades when the number of peptide chemists and biologists increased to such an extent that their enumeration would have gone beyond the scope of this Appendix. 250 Appendix Plate 8. Emil Abderhalden (1877-1950), Photo Plate 9. S. Akabori Leopoldina, Halle J Plate 10. Ernst Bayer Plate 11. Karel Blaha (1926-1988) Appendix 251 Plate 12. Max Brenner Plate 13. Hans Brockmann (1903-1988) Plate 14. Victor Bruckner (1900- 1980) Plate 15. Pehr V. Edman (1916- 1977) 252 Appendix Plate 16. Lyman C. Craig (1906-1974) Plate 17. Vittorio Erspamer Plate 18. Joseph S. Fruton, Biochemist and Historian Appendix 253 Plate 19. Rolf Geiger (1923-1988) Plate 20. Wolfgang Konig Plate 21. Dorothy Hodgkins Plate. 22. Franz Hofmeister (1850-1922), (Fischer, biograph. Lexikon) 254 Appendix Plate 23. The picture shows the late Professor 1.E. Jorpes (r.j and Professor V. Mutt during their favorite pastime in the archipelago on the Baltic near Stockholm Plate 24. Ephraim Katchalski (Katzir) Plate 25. Abraham Patchornik Appendix 255 Plate 26. P.G. Katsoyannis Plate 27. George W. Kenner (1922-1978) Plate 28. Edger Lederer (1908- 1988) Plate 29. Hennann Leuchs (1879-1945) 256 Appendix Plate 30. Choh Hao Li (1913-1987) Plate 31. -
A Global Review on Short Peptides: Frontiers and Perspectives †
molecules Review A Global Review on Short Peptides: Frontiers and Perspectives † Vasso Apostolopoulos 1 , Joanna Bojarska 2,* , Tsun-Thai Chai 3 , Sherif Elnagdy 4 , Krzysztof Kaczmarek 5 , John Matsoukas 1,6,7, Roger New 8,9, Keykavous Parang 10 , Octavio Paredes Lopez 11 , Hamideh Parhiz 12, Conrad O. Perera 13, Monica Pickholz 14,15, Milan Remko 16, Michele Saviano 17, Mariusz Skwarczynski 18, Yefeng Tang 19, Wojciech M. Wolf 2,*, Taku Yoshiya 20 , Janusz Zabrocki 5, Piotr Zielenkiewicz 21,22 , Maha AlKhazindar 4 , Vanessa Barriga 1, Konstantinos Kelaidonis 6, Elham Mousavinezhad Sarasia 9 and Istvan Toth 18,23,24 1 Institute for Health and Sport, Victoria University, Melbourne, VIC 3030, Australia; [email protected] (V.A.); [email protected] (J.M.); [email protected] (V.B.) 2 Institute of General and Ecological Chemistry, Faculty of Chemistry, Lodz University of Technology, Zeromskiego˙ 116, 90-924 Lodz, Poland 3 Department of Chemical Science, Faculty of Science, Universiti Tunku Abdul Rahman, Kampar 31900, Malaysia; [email protected] 4 Botany and Microbiology Department, Faculty of Science, Cairo University, Gamaa St., Giza 12613, Egypt; [email protected] (S.E.); [email protected] (M.A.) 5 Institute of Organic Chemistry, Faculty of Chemistry, Lodz University of Technology, Zeromskiego˙ 116, 90-924 Lodz, Poland; [email protected] (K.K.); [email protected] (J.Z.) 6 NewDrug, Patras Science Park, 26500 Patras, Greece; [email protected] 7 Department of Physiology and Pharmacology, -
Induction of Tumor Apoptosis Through a Circular RNA Enhancing Foxo3 Activity
Cell Death and Differentiation (2017) 24, 357–370 & 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved 1350-9047/17 www.nature.com/cdd Induction of tumor apoptosis through a circular RNA enhancing Foxo3 activity William W Du1,2,5, Ling Fang1,2,3,5, Weining Yang1,5, Nan Wu1,2, Faryal Mehwish Awan1,2, Zhenguo Yang1,2 and Burton B Yang*,1,2,4 Circular RNAs are a class of non-coding RNAs that are receiving extensive attention. Despite reports showing circular RNAs acting as microRNA sponges, the biological functions of circular RNAs remain largely unknown. We show that in patient tumor samples and in a panel of cancer cells, circ-Foxo3 was minimally expressed. Interestingly, during cancer cell apoptosis, the expression of circ-Foxo3 was found to be significantly increased. We found that silencing endogenous circ-Foxo3 enhanced cell viability, whereas ectopic expression of circ-Foxo3 triggered stress-induced apoptosis and inhibited the growth of tumor xenografts. Also, expression of circ-Foxo3 increased Foxo3 protein levels but repressed p53 levels. By binding to both, circ-Foxo3 promoted MDM2-induced p53 ubiquitination and subsequent degradation, resulting in an overall decrease of p53. With low binding affinity to Foxo3 protein, circ-Foxo3 prevented MDM2 from inducing Foxo3 ubiquitination and degradation, resulting in increased levels of Foxo3 protein. As a result, cell apoptosis was induced by upregulation of the Foxo3 downstream target PUMA. Cell Death and Differentiation (2017) 24, 357–370; doi:10.1038/cdd.2016.133; published online 25 November 2016 Circular RNAs are a large class of non-coding RNAs that are Results circularized by joining free 3'- to 5'-ends, forming a circular structure.1–4 Although circular RNAs were initially Decreased expression of circ-Foxo3 in tumors and characterized over 30 years ago, their functions in mammalian cancer cells. -
Stapled Peptides—A Useful Improvement for Peptide-Based Drugs
molecules Review Stapled Peptides—A Useful Improvement for Peptide-Based Drugs Mattia Moiola, Misal G. Memeo and Paolo Quadrelli * Department of Chemistry, University of Pavia, Viale Taramelli 12, 27100 Pavia, Italy; [email protected] (M.M.); [email protected] (M.G.M.) * Correspondence: [email protected]; Tel.: +39-0382-987315 Received: 30 July 2019; Accepted: 1 October 2019; Published: 10 October 2019 Abstract: Peptide-based drugs, despite being relegated as niche pharmaceuticals for years, are now capturing more and more attention from the scientific community. The main problem for these kinds of pharmacological compounds was the low degree of cellular uptake, which relegates the application of peptide-drugs to extracellular targets. In recent years, many new techniques have been developed in order to bypass the intrinsic problem of this kind of pharmaceuticals. One of these features is the use of stapled peptides. Stapled peptides consist of peptide chains that bring an external brace that force the peptide structure into an a-helical one. The cross-link is obtained by the linkage of the side chains of opportune-modified amino acids posed at the right distance inside the peptide chain. In this account, we report the main stapling methodologies currently employed or under development and the synthetic pathways involved in the amino acid modifications. Moreover, we report the results of two comparative studies upon different kinds of stapled-peptides, evaluating the properties given from each typology of staple to the target peptide and discussing the best choices for the use of this feature in peptide-drug synthesis. Keywords: stapled peptide; structurally constrained peptide; cellular uptake; helicity; peptide drugs 1. -
Glossary of Hazardous Materials Terms
GLOSSARY OF CHEMICAL HAZARD TERMS ACGIH - The American Conference of Governmental Industrial Hygienists consists of occupational safety and health professionals who recommend occupational exposure limits for many substances. Action Level - An OSHA concentration calculated as an 8-your time-weighted average, which initiates certain required activities such as exposure monitoring and medical surveillance. Acute Health Effect - A severe effect which occurs rapidly after a brief intense exposure to a substance. ANSI - American National Standards Institute is a private group that develops consensus standards. Acute toxicity -Acutely toxic substances cause adverse effects by any of the following exposure methods: 1. Oral or dermal administration of a single dose of a substance. 2. Multiple oral or dermal doses within a 24-hour period 3. An inhalation exposure of 4 hours. Asphyxiant - A chemical (gas or vapor) that can cause death or unconsciousness by suffocation. Aspiration hazard - A liquid or solid chemical that causes severe acute effects if it infiltrates into the trachea and lower respiratory tract. Possible effects include chemical pneumonia, pulmonary injury, or death Autoignition Temperature - The lowest temperature at which a substance will burst into flames without a source of ignition like a spark or flame. The lower the ignition temperature, the more likely the substance is going to be a fire hazard. Boiling Point - The temperature of a liquid at which its vapor pressure is equal to the gas pressure over it. With added energy, all of the liquid could become vapor. Boiling occurs when the liquid's vapor pressure is just higher than the pressure over it. Carcinogen - A substance that causes cancer in humans or, because it has produced cancer in animals, is considered capable of causing cancer in humans. -
Analyzing Binding Data UNIT 7.5 Harvey J
Analyzing Binding Data UNIT 7.5 Harvey J. Motulsky1 and Richard R. Neubig2 1GraphPad Software, La Jolla, California 2University of Michigan, Ann Arbor, Michigan ABSTRACT Measuring the rate and extent of radioligand binding provides information on the number of binding sites, and their afÞnity and accessibility of these binding sites for various drugs. This unit explains how to design and analyze such experiments. Curr. Protoc. Neurosci. 52:7.5.1-7.5.65. C 2010 by John Wiley & Sons, Inc. Keywords: binding r radioligand r radioligand binding r Scatchard plot r r r r r r receptor binding competitive binding curve IC50 Kd Bmax nonlinear regression r curve Þtting r ßuorescence INTRODUCTION A radioligand is a radioactively labeled drug that can associate with a receptor, trans- porter, enzyme, or any protein of interest. The term ligand derives from the Latin word ligo, which means to bind or tie. Measuring the rate and extent of binding provides information on the number, afÞnity, and accessibility of these binding sites for various drugs. While physiological or biochemical measurements of tissue responses to drugs can prove the existence of receptors, only ligand binding studies (or possibly quantitative immunochemical studies) can determine the actual receptor concentration. Radioligand binding experiments are easy to perform, and provide useful data in many Þelds. For example, radioligand binding studies are used to: 1. Study receptor regulation, for example during development, in diseases, or in response to a drug treatment. 2. Discover new drugs by screening for compounds that compete with high afÞnity for radioligand binding to a particular receptor. -
International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification
0031-6997/03/5504-597–606$7.00 PHARMACOLOGICAL REVIEWS Vol. 55, No. 4 Copyright © 2003 by The American Society for Pharmacology and Experimental Therapeutics 30404/1114803 Pharmacol Rev 55:597–606, 2003 Printed in U.S.A International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification. XXXVIII. Update on Terms and Symbols in Quantitative Pharmacology RICHARD R. NEUBIG, MICHAEL SPEDDING, TERRY KENAKIN, AND ARTHUR CHRISTOPOULOS Department of Pharmacology, University of Michigan, Ann Arbor, Michigan (R.R.N.); Institute de Recherches Internationales Servier, Neuilly sur Seine, France (M.S.); Systems Research, GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina (T.K.); and Department of Pharmacology, University of Melbourne, Parkville, Australia (A.C.) Abstract ............................................................................... 597 I. Introduction............................................................................ 597 II. Working definition of a receptor .......................................................... 598 III. Use of drugs in definition of receptors or of signaling pathways ............................. 598 A. The expression of amount of drug: concentration and dose ............................... 598 1. Concentration..................................................................... 598 2. Dose. ............................................................................ 598 B. General terms used to describe drug action ........................................... -
Amino Acids-The Molecular Building Blocks of Life
Understanding the structure-property relationships of amino acids-the molecular building blocks of life Aravindhan Ganesan Dissertation submitted in fulfillment of requirements for the degree of Doctor of Philosophy Environmental and Biotechnology Centre Faculty of Life & Social Sciences Swinburne University of Technology Victoria, Australia 2013 ©2013 Aravindhan Ganesan Abstract Amino acids are significant molecular building blocks of proteins. Only 20 natural amino acids, whose structures differ in their side chain ‘R-’ groups, control the structures, functions and selectivity of almost all the proteins in biology. The structure-properties of the amino acids must be revealed, in order to understand the methodical behind the nature’s choices in using them as ‘building blocks’. There are several molecular level details of the amino acids, which are still unknown or limitedly known. In this project, the electronic structures, properties and dynamics of the aliphatic and the aromatic amino acids under isolated and defined environmental conditions are studied quantum mechanically. A rich tool chest of ab initio and density functional theory (DFT) methods has been employed. The impacts of alkyl side chain groups on the structure-properties of the aliphatic amino acids are revealed in the gas phase. A number of properties including geometries, molecular dipole moments, ionization energies and spectra, charge re-distributions, vibrational spectra (IR and Raman), vibrational optical activity spectra (VOA), molecular orbitals and momentum spectra are investigated. Dual space analyses (DSA) has been employed as an efficient analytical tool to understand the electronic structures of the amino acids in both the coordinate space and momentum space. Our quantum chemical calculations are validated against the synchrotron-sourced and other experiments, whenever possible. -
© Copyright 2012 Craig J. Bierle Portions of This Dissertation Were
© Copyright 2012 Craig J. Bierle Portions of this dissertation were adapted from the following publications: Copyright © American Society for Microbiology Journal of Virology, May 2009, p. 4112–4120 Vol. 83, No. 9 doi:10.1128/JVI.02489-08 Copyright © Elsevier Inc. Virology, November 2012, p. 157–166, Vol. 433 Iss. 1 http://dx.doi.org/10.1016/j.virol.2012.08.005 Inhibition of the protein kinase R pathway by cytomegalovirus double-stranded RNA binding proteins Craig J. Bierle A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Washington 2012 Reading Committee: Adam P. Geballe, Chair Michael Lagunoff Harmit S. Malik Program Authorized to Offer Degree: Molecular and Cellular Biology University of Washington Abstract Inhibition of the protein kinase R pathway by cytomegalovirus double-stranded RNA binding proteins Craig J. Bierle Chair of the Supervisory Committee: Professor Adam P. Geballe Division of Human Biology Double-stranded RNA (dsRNA) that accumulates during many viral infections is recognized by the host cell and elicits an antiviral response. Protein kinase R (PKR) is activated by dsRNA binding, phosphorylates eIF2α, and inhibits translation initiation, potentially blocking the synthesis of viral proteins. Human cytomegalovirus (HCMV) expresses two noncanonical dsRNA binding proteins, TRS1 and IRS, that antagonize PKR. In this study, I investigated the dsRNA-binding properties of TRS1 and related proteins to help clarify their mechanisms of PKR inhibition and roles in viral replication. I found that purified TRS1 specifically bound to dsRNAs as short as 20 base pairs, albeit with a weaker affinity than PKR. -
First Principles and Their Application to Drug Discovery
REVIEWS Drug Discovery Today Volume 17, Numbers 1/2 January 2012 The utilization of the kinetic and thermodynamic signatures of preclinical leads is proving pivotal in their triage and rational optimization towards clinical candidates with maximal in vivo efficacy devoid of adverse events. Reviews KEYNOTE REVIEW Target–drug interactions: first principles and their application to drug discovery 1 1 Sara Nu´n˜ez studied organic Sara Nu´n˜ ez , Jennifer Venhorst and Chris G. Kruse chemistry at the University of Barcelona (Spain) and the Abbott Healthcare Products, 1381 CP Weesp, The Netherlands University of London (UK). She received her Ph.D. in 2003 from the University of Manchester (UK), and thereafter did a In this review, we begin by introducing the basic principles of kinetics postdoc in Biophysics at the and thermodynamics of target–drug binding within the context of Albert Einstein College of Medicine (USA). In 2005, she drug discovery. In addition, we present a meta-analysis of the recent joined Solvay Pharmaceuticals (now Abbott Healthcare) in The Netherlands as a postdoctoral fellow; and in 2008, she literature describing the kinetic and thermodynamic resolution of was promoted to Sr. Computational Medicinal Chemist. At Abbott, she has supported the medicinal chemistry efforts successful clinical candidates with diverse mechanisms of action. for neuroscience drug discovery programs, from target We finish by discussing the best practices in the triage and chemical discovery up to and including clinical proof of principle studies. She has supported more than 15 programs optimization towards clinical candidates with maximal in vivo internationally, and was project manager of the D2-103 Top Institute Pharma innitiative.