Structure and Evolution of Protein Allosteric Sites
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Allosteric Regulation in Drug Design
Mini Review Curr Trends Biomedical Eng & Biosci Volume 4 Issue 1 - May 2017 Copyright © All rights are reserved by Ashfaq Ur Rehman DOI: 10.19080/CTBEB.2017.04.5555630 Allosteric regulation in drug design Ashfaq Ur Rehman1,2*, Shah Saud3, Nasir Ahmad4, Abdul Wadood2 and R Hamid5 1State Key Laboratory of Microbial Metabolism, Department of Bioinformatics and Biostatistics, China 2Department of Biochemistry, Abdul Wali Khan University Mardan, Pakistan 3Laboratory of Analytical Biochemistry and Bio separation, Shanghai Jiao Tong University, China 4Department of Chemistry, Islama College University Peshawar, Pakistan 5Department of Bioinformatics, Muhammad Ali Jinnah University Islamabad, Pakistan Submission: May 02, 2017; Published: May 23, 2017 *Corresponding author: Ashfaq Ur Rehman, State Key Laboratory of Microbial Metabolism, Department of Bioinformatics and Biostatistics, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China, Tel: ; Fax: 86-21-34204348; Email: Abstract mechanism, which are initiated through attachment of ligand or inhibitors with the protein or enzymes other than active (orthosteric) sites. ThisProtein mini review and enzymes involved play mechanism, significant types roles and in importancebiological processes of allosteric of all regulations living organisms; in drug theirdesign functions process. are regulated through allosteric Keywords: Allosteric, Activator: Drug design Introduction and ultimately cause disease. While various biological processes expressed the control at different points in life time of protein function is pivotal. As all the cell processes are under carful For the survival of all organisms the significance of protein included regulation of gene expression, translation into protein control and if not properly controls this leads to the abnormality through control of activity and at last degradation of protein [1]. -
Tyrosine Kinase – Role and Significance in Cancer
Int. J. Med. Sci. 2004 1(2): 101-115 101 International Journal of Medical Sciences ISSN 1449-1907 www.medsci.org 2004 1(2):101-115 ©2004 Ivyspring International Publisher. All rights reserved Review Tyrosine kinase – Role and significance in Cancer Received: 2004.3.30 Accepted: 2004.5.15 Manash K. Paul and Anup K. Mukhopadhyay Published:2004.6.01 Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Sector-67, S.A.S Nagar, Mohali, Punjab, India-160062 Abstract Tyrosine kinases are important mediators of the signaling cascade, determining key roles in diverse biological processes like growth, differentiation, metabolism and apoptosis in response to external and internal stimuli. Recent advances have implicated the role of tyrosine kinases in the pathophysiology of cancer. Though their activity is tightly regulated in normal cells, they may acquire transforming functions due to mutation(s), overexpression and autocrine paracrine stimulation, leading to malignancy. Constitutive oncogenic activation in cancer cells can be blocked by selective tyrosine kinase inhibitors and thus considered as a promising approach for innovative genome based therapeutics. The modes of oncogenic activation and the different approaches for tyrosine kinase inhibition, like small molecule inhibitors, monoclonal antibodies, heat shock proteins, immunoconjugates, antisense and peptide drugs are reviewed in light of the important molecules. As angiogenesis is a major event in cancer growth and proliferation, tyrosine kinase inhibitors as a target for anti-angiogenesis can be aptly applied as a new mode of cancer therapy. The review concludes with a discussion on the application of modern techniques and knowledge of the kinome as means to gear up the tyrosine kinase drug discovery process. -
DNA Breakpoint Assay Reveals a Majority of Gross Duplications Occur in Tandem Reducing VUS Classifications in Breast Cancer Predisposition Genes
© American College of Medical Genetics and Genomics ARTICLE Corrected: Correction DNA breakpoint assay reveals a majority of gross duplications occur in tandem reducing VUS classifications in breast cancer predisposition genes Marcy E. Richardson, PhD1, Hansook Chong, PhD1, Wenbo Mu, MS1, Blair R. Conner, MS1, Vickie Hsuan, MS1, Sara Willett, MS1, Stephanie Lam, MS1, Pei Tsai, CGMBS, MB (ASCP)1, Tina Pesaran, MS, CGC1, Adam C. Chamberlin, PhD1, Min-Sun Park, PhD1, Phillip Gray, PhD1, Rachid Karam, MD, PhD1 and Aaron Elliott, PhD1 Purpose: Gross duplications are ambiguous in terms of clinical cohort, while the remainder have unknown tandem status. Among interpretation due to the limitations of the detection methods that the tandem gross duplications that were eligible for reclassification, cannot infer their context, namely, whether they occur in tandem or 95% of them were upgraded to pathogenic. are duplicated and inserted elsewhere in the genome. We Conclusion: DBA is a novel, high-throughput, NGS-based method investigated the proportion of gross duplications occurring in that informs the tandem status, and thereby the classification of, tandem in breast cancer predisposition genes with the intent of gross duplications. This method revealed that most gross duplica- informing their classifications. tions in the investigated genes occurred in tandem and resulted in a Methods: The DNA breakpoint assay (DBA) is a custom, paired- pathogenic classification, which helps to secure the necessary end, next-generation sequencing (NGS) method designed to treatment options for their carriers. capture and detect deep-intronic DNA breakpoints in gross duplications in BRCA1, BRCA2, ATM, CDH1, PALB2, and CHEK2. Genetics in Medicine (2019) 21:683–693; https://doi.org/10.1038/s41436- Results: DBA allowed us to ascertain breakpoints for 44 unique 018-0092-7 gross duplications from 147 probands. -
Integrated Computational Approaches and Tools for Allosteric Drug Discovery
International Journal of Molecular Sciences Review Integrated Computational Approaches and Tools for Allosteric Drug Discovery Olivier Sheik Amamuddy 1 , Wayde Veldman 1 , Colleen Manyumwa 1 , Afrah Khairallah 1 , Steve Agajanian 2, Odeyemi Oluyemi 2, Gennady M. Verkhivker 2,3,* and Özlem Tastan Bishop 1,* 1 Research Unit in Bioinformatics (RUBi), Department of Biochemistry and Microbiology, Rhodes University, Grahamstown 6140, South Africa; [email protected] (O.S.A.); [email protected] (W.V.); [email protected] (C.M.); [email protected] (A.K.) 2 Graduate Program in Computational and Data Sciences, Keck Center for Science and Engineering, Schmid College of Science and Technology, Chapman University, One University Drive, Orange, CA 92866, USA; [email protected] (S.A.); [email protected] (O.O.) 3 Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Irvine, CA 92618, USA * Correspondence: [email protected] (G.M.V.); [email protected] (Ö.T.B.); Tel.: +714-516-4586 (G.M.V.); +27-46-603-8072 (Ö.T.B.) Received: 25 December 2019; Accepted: 21 January 2020; Published: 28 January 2020 Abstract: Understanding molecular mechanisms underlying the complexity of allosteric regulation in proteins has attracted considerable attention in drug discovery due to the benefits and versatility of allosteric modulators in providing desirable selectivity against protein targets while minimizing toxicity and other side effects. The proliferation of novel computational approaches for predicting ligand–protein interactions and binding using dynamic and network-centric perspectives has led to new insights into allosteric mechanisms and facilitated computer-based discovery of allosteric drugs. Although no absolute method of experimental and in silico allosteric drug/site discovery exists, current methods are still being improved. -
Statistical Mechanics of Allosteric Enzymes
Statistical Mechanics of Allosteric Enzymes Tal Einav,† Linas Mazutis,‡ and Rob Phillips∗,¶ Department of Physics, California Institute of Technology, Pasadena, California 91125, United States, Institute of Biotechnology, Vilnius University, Vilnius, Lithuania, and Department of Applied Physics and Division of Biology, California Institute of Technology, Pasadena, California 91125, United States E-mail: [email protected] Abstract The concept of allostery in which macromolecules switch between two different conforma- tions is a central theme in biological processes ranging from gene regulation to cell signaling to enzymology. Allosteric enzymes pervade metabolic processes, yet a simple and unified treatment of the effects of allostery in enzymes has been lacking. In this work, we take the first step towards this goal by modeling allosteric enzymes and their interaction with two key molecular players - allosteric regulators and competitive inhibitors. We then apply this model to characterize existing data on enzyme activity, comment on how enzyme parameters (such as substrate binding affinity) can be experimentally tuned, and make novel predictions on how to control phenomena such as substrate inhibition. arXiv:1701.03988v1 [q-bio.SC] 15 Jan 2017 ∗To whom correspondence should be addressed †Department of Physics, California Institute of Technology, Pasadena, California 91125, United States ‡Institute of Biotechnology, Vilnius University, Vilnius, Lithuania ¶Department of Applied Physics and Division of Biology, California Institute -
Lec-08-Handout
NPTEL VIDEO COURSE – PROTEOMICS PROF. SANJEEVA SRIVASTAVA HANDOUT LECTURE-08 ENZYME: BASIC CONCEPTS, CATALYTIC AND REGULATORY STRATEGIES Slide 1 Today, we will talk about enzyme: basic concepts, catalytic and regulatory strategies. Slide 2 Lecture outline: • Basic concepts of enzyme including enzyme kinetics, energetics and enzyme inhibition. • Different type of catalytic strategies and regulatory strategies. Slide 3 So as you all know, enzymes play very important role in biochemistry All enzymes are proteins therefore it will essential to study about enzymes while studying basic concepts of amino acids and proteins. Although it may not be directly linked to the proteomics but understanding of enzyme and proteins is very fundamental for the advanced understanding of concepts related to proteomics. Slide 4 So what are enzymes? • Enzymes are molecular catalysts. • Almost all enzymes are proteins and as we have discussed in the previous lecture there are twenty amino acids that make up the basic building blocks of all proteins. • Enzymes can accelerate a given reaction up to million folds. Let’s take an example of carbonic anhydrase which catalyzes hydration of carbon di oxide. Now this enzyme can catalyze 106 molecules per second. • Enzymes are highly specific and catalyze single or closely related reaction. DEPARTMENT OF BIOSCIENCES & BIOENGINEERING INDIAN INSTITUTE OF TECHNOLOGY (IIT) BOMBAY, MUMBAI, INDIA Page 1 NPTEL VIDEO COURSE – PROTEOMICS PROF. SANJEEVA SRIVASTAVA Slide 5 In terms of enzyme specificity, let me give you few examples- • Trypsin- it is highly specific, it cleaves peptide on carboxyl side of Lys/Arg. • Another enzyme thrombin, which participates in blood clotting, it is even more specific that trypsin. -
Tyrosine Kinases
KEVANM SHOKAT MINIREVIEW Tyrosine kinases: modular signaling enzymes with tunable specificities Cytoplasmic tyrosine kinases are composed of modular domains; one (SHl) has catalytic activity, the other two (SH2 and SH3) do not. Kinase specificity is largely determined by the binding preferences of the SH2 domain. Attaching the SHl domain to a new SH2 domain, via protein-protein association or mutation, can thus dramatically change kinase function. Chemistry & Biology August 1995, 2:509-514 Protein kinases are one of the largest protein families identified, This is a result of the overlapping substrate identified to date; over 45 new members are identified specificities of many tyrosine kinases, which makes it each year. It is estimated that up to 4 % of vertebrate pro- difficult to dissect the individual signaling pathways by teins are protein kinases [l].The protein kinases are cate- scanning for unique target motifs [2]. gorized by their specificity for serineithreonine, tyrosine, or histidine residues. Protein tyrosine kinases account for The apparent promiscuity of individual tyrosine kinases roughly half of all kinases. They occur as membrane- is a result of their unique structural organization. bound receptors or cytoplasmic proteins and are involved Enzyme specificity is typically programmed by one in a wide variety of cellular functions, including cytokine binding site, which recognizes the substrate and also con- responses, antigen-dependent immune responses, cellular tains exquisitely oriented active-site functional groups transformation by RNA viruses, oncogenesis, regulation that help to lower the energy of the transition state for of the cell cycle, and modification of cell morphology the conversion of specific substrates to products.Tyrosine (Fig. -
Understanding Drug-Drug Interactions Due to Mechanism-Based Inhibition in Clinical Practice
pharmaceutics Review Mechanisms of CYP450 Inhibition: Understanding Drug-Drug Interactions Due to Mechanism-Based Inhibition in Clinical Practice Malavika Deodhar 1, Sweilem B Al Rihani 1 , Meghan J. Arwood 1, Lucy Darakjian 1, Pamela Dow 1 , Jacques Turgeon 1,2 and Veronique Michaud 1,2,* 1 Tabula Rasa HealthCare Precision Pharmacotherapy Research and Development Institute, Orlando, FL 32827, USA; [email protected] (M.D.); [email protected] (S.B.A.R.); [email protected] (M.J.A.); [email protected] (L.D.); [email protected] (P.D.); [email protected] (J.T.) 2 Faculty of Pharmacy, Université de Montréal, Montreal, QC H3C 3J7, Canada * Correspondence: [email protected]; Tel.: +1-856-938-8697 Received: 5 August 2020; Accepted: 31 August 2020; Published: 4 September 2020 Abstract: In an ageing society, polypharmacy has become a major public health and economic issue. Overuse of medications, especially in patients with chronic diseases, carries major health risks. One common consequence of polypharmacy is the increased emergence of adverse drug events, mainly from drug–drug interactions. The majority of currently available drugs are metabolized by CYP450 enzymes. Interactions due to shared CYP450-mediated metabolic pathways for two or more drugs are frequent, especially through reversible or irreversible CYP450 inhibition. The magnitude of these interactions depends on several factors, including varying affinity and concentration of substrates, time delay between the administration of the drugs, and mechanisms of CYP450 inhibition. Various types of CYP450 inhibition (competitive, non-competitive, mechanism-based) have been observed clinically, and interactions of these types require a distinct clinical management strategy. This review focuses on mechanism-based inhibition, which occurs when a substrate forms a reactive intermediate, creating a stable enzyme–intermediate complex that irreversibly reduces enzyme activity. -
Metabolism of Glycogen Glycogenesis
LEC: 10Biochemistry Dr. Anwar J Almzaiel Metabolism of glycogen Glycogen is the major storage form of carbohydrate in animal and corresponds to starch in plant. It occurs mainly in liver (up to 6%) and muscle(up to 1%). However, because of great mass, muscle represents some 3-4 times as much as glycogen store as liver. It is branched polymer of α- glucose. The function of muscle glycogen is to act as a readily available source of hexose units for glycolysis within the muscle itself. Liver glycogen is largely concerned with storage and export of hexose units for maintenance of the blood glucose, particularly between meals. After (12-18 hours) of fasting, the liver becomes almost totally depleted of glycogen, whereas muscle glycogen is only depleted significantly after prolonged various exercise. Why the cell can store glycogen but not glucose? Because when glucose increased, osmatic pressure in the cell increase, causing water movement toward the cell and leading to burst so when glucose accumulates in the cell, it will convert to glycogen which consists of branched series of glucose. Glycogenesis The process of glycogenesis start when glucose-6-phosphat is changed to glucose-1-phosphate by mutase mutas glucose-6-phosphatglucosee 1-phosphate The reaction is reversible and depends on concentration of substrate (glucose- 6-phosphat), if there is a large amount or quantities of glucose-6-phosphat will lead to formation of glucose 1-phosphate and the opposite is right. No loss in the energy in this reaction As glucose 1-phosphate formed, it will react with high energy compound UTP (uradin triphosphate), which react with glucose to give UDP glucose (uradin diphosphate glucose) and pyrophosphate released glucose 1-phosphate is high energetic compound and called (active glucose molecule), this reaction is carried by (UDP glucose pyrophosphorylase) 1 LEC: 10Biochemistry Dr. -
Spring 2013 Lecture 13-14
CHM333 LECTURE 13 – 14: 2/13 – 15/13 SPRING 2013 Professor Christine Hrycyna INTRODUCTION TO ENZYMES • Enzymes are usually proteins (some RNA) • In general, names end with suffix “ase” • Enzymes are catalysts – increase the rate of a reaction – not consumed by the reaction – act repeatedly to increase the rate of reactions – Enzymes are often very “specific” – promote only 1 particular reaction – Reactants also called “substrates” of enzyme catalyst rate enhancement non-enzymatic (Pd) 102-104 fold enzymatic up to 1020 fold • How much is 1020 fold? catalyst time for reaction yes 1 second no 3 x 1012 years • 3 x 1012 years is 500 times the age of the earth! Carbonic Anhydrase Tissues ! + CO2 +H2O HCO3− +H "Lungs and Kidney 107 rate enhancement Facilitates the transfer of carbon dioxide from tissues to blood and from blood to alveolar air Many enzyme names end in –ase 89 CHM333 LECTURE 13 – 14: 2/13 – 15/13 SPRING 2013 Professor Christine Hrycyna Why Enzymes? • Accelerate and control the rates of vitally important biochemical reactions • Greater reaction specificity • Milder reaction conditions • Capacity for regulation • Enzymes are the agents of metabolic function. • Metabolites have many potential pathways • Enzymes make the desired one most favorable • Enzymes are necessary for life to exist – otherwise reactions would occur too slowly for a metabolizing organis • Enzymes DO NOT change the equilibrium constant of a reaction (accelerates the rates of the forward and reverse reactions equally) • Enzymes DO NOT alter the standard free energy change, (ΔG°) of a reaction 1. ΔG° = amount of energy consumed or liberated in the reaction 2. -
Allosteric Enzymes: Properties and Mechanism | Microbiology
Allosteric Enzymes: Properties and Mechanism | Microbiology In this article we will discuss about the properties and mechanisms of action of allosteric enzymes. Properties of Allosteric Enzymes: Allosteric or Regulatory enzymes have multiple subunits (Quaternary Structure) and multiple active sites. Allosteric enzymes have active and inactive shapes differing in 3D structure. Allosteric enzymes often have multiple inhibitor or activator binding sites involved in switching between active and inactive shapes. Allosteric enzymes have characteristic “S”-shaped curve for reaction rate vs. substrate concentration. Why? Because the substrate binding is “Cooperative.” And the binding of first substrate at first active site stimulates active shapes, and promotes binding of second substrate. A modulator is a me-tabolite, when bound to the allosteric site of an enzyme, alters its kinetic characteristics. The modulators for allosteric enzyme may be ei-ther stimulatory or inhibitory. A stimulator is often the sub-strate itself. The regulatory enzymes for which substrate and modulator are identical are called homo-tropic. When the modulator has a structure different then the substrate, the enzyme is called heterotropic. Some enzymes have more then one modulators. The allosteric enzymes also have one or more regulatory or aliosteric sites for binding the modulator. Enzymes with several modulators generally have different specific binding sites for each (Fig. 12.15). The sigmoid curve is given by homo-tropic enzymes in which the substrate also serve as a positive (stimulator) modu-lator (12.16). Curve for the non-regulatory enzymes is hy-perbolic, as also predicted by the Michaelis-Menten equa-tion, whereas allosteric en-zymes do not show Michaelis- Menten relationship because their kinetic behaviour is greatly altered by variation in the concentration of modula-tors. -
Druggable Transient Pockets in Protein Kinases
molecules Review Druggable Transient Pockets in Protein Kinases Koji Umezawa 1 and Isao Kii 2,* 1 Department of Biomolecular Innovation, Institute for Biomedical Sciences, Shinshu University, 8304 Minami-Minowa, Kami-ina, Nagano 399-4598, Japan; [email protected] 2 Laboratory for Drug Target Research, Faculty & Graduate School of Agriculture, Shinshu University, 8304 Minami-Minowa, Kami-ina, Nagano 399-4598, Japan * Correspondence: [email protected]; Tel.: +81-265-77-1521 Abstract: Drug discovery using small molecule inhibitors is reaching a stalemate due to low se- lectivity, adverse off-target effects and inevitable failures in clinical trials. Conventional chemical screening methods may miss potent small molecules because of their use of simple but outdated kits composed of recombinant enzyme proteins. Non-canonical inhibitors targeting a hidden pocket in a protein have received considerable research attention. Kii and colleagues identified an inhibitor targeting a transient pocket in the kinase DYRK1A during its folding process and termed it FINDY. FINDY exhibits a unique inhibitory profile; that is, FINDY does not inhibit the fully folded form of DYRK1A, indicating that the FINDY-binding pocket is hidden in the folded form. This intriguing pocket opens during the folding process and then closes upon completion of folding. In this review, we discuss previously established kinase inhibitors and their inhibitory mechanisms in comparison with FINDY. We also compare the inhibitory mechanisms with the growing concept of “cryptic inhibitor-binding sites.” These sites are buried on the inhibitor-unbound surface but become apparent when the inhibitor is bound. In addition, an alternative method based on cell-free protein synthesis of protein kinases may allow the discovery of small molecules that occupy these mysterious binding sites.