G Protein-Coupled Receptors: From Structure to Function (RSC Drug Discovery) - Hardcover

 
9781849731836: G Protein-Coupled Receptors: From Structure to Function (RSC Drug Discovery)
Hardcover
ISBN 10: 1849731837 ISBN 13: 9781849731836
Verlag: Royal Society of Chemistry, 2011

Inhaltsangabe

G protein-coupled receptors (GPCRs) are the largest family of cell-surface receptors, with more than 800 members identified thus far in the human genome. They regulate the function of most cells in the body, and represent approximately 3% of the genes in the human genome. These receptors respond to a wide variety of structurally diverse ligands, ranging from small molecules, such as biogenic amines, nucleotides and ions, to lipids, peptides, proteins, and even light. Ligands (agonists and antagonists) acting on GPCRs are important in the treatment of numerous diseases, including cardiovascular and mental disorders, retinal degeneration, cancer, and AIDS. It is estimated that these receptors represent about one third of the actual identified targets of clinically used drugs. The determination of rhodopsin crystal structure and, more recently, of opsin, 1 and 2 adrenergic and A2A adenosine receptors provides both academia and industry with extremely valuable data for a better understanding of the molecular determinants of receptor function and a more reliable rationale for drug design. GPCR structure and function constitutes a hot topic. The book, which lies between the fields of chemical biology, molecular pharmacology and medicinal chemistry, is divided into three parts. The first part considers what receptor structures tell us about the mechanism of receptor activation. Part II focuses on receptor function. It discusses what the data from biophysical and mutational studies, and the analysis of the interactions of the receptor with ligands and regulator proteins, tell us about the process of signal transduction. The final part, on modelling and simulation, details new insights on the link between structure and mechanism and their implications in drug design.

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Über die Autorinnen und Autoren

Jes·s Giraldo is based at the Institut de NeurociÞncies and Unitat de BioestadÝstica, Universitat Aut=noma de Barcelona. He works mainly in the field of mathematical modelling of GPCRs and has collaborated with a number of experimentalists, some of them leaders in the GPCR field. This has given him a deep understanding of the relationships between theory and experimentation in the area and a holistic view of the topic. Jean-Philippe Pin got his PhD in Molecular Biology from the University of Montpellier 2, France. He participated in the discovery of the metabotropic glutamate receptors and demonstrated synergism between various glutamate receptor subtypes for the activation of phospholipase A2. Subsequently, he worked as a post doctoral fellow at the Salk Institute where he cloned and characterized new mGlu receptor splice variants. In 1992, he set up a research team working on the structure function relationship of mGlu receptors in the CNRS laboratory in Montpellier. Currently, he heads the Molecular Pharmacology Department within the Institute of Functional Genomics, Montpellier, France where his research focuses on the molecular and cellular dynamics of GPCRs and has led to major new concepts in the GPCR field.



Jes·s Giraldo is based at the Institut de NeurociÞncies and Unitat de BioestadÝstica, Universitat Aut=noma de Barcelona. He works mainly in the field of mathematical modelling of GPCRs and has collaborated with a number of experimentalists, some of them leaders in the GPCR field. This has given him a deep understanding of the relationships between theory and experimentation in the area and a holistic view of the topic. Jean-Philippe Pin got his PhD in Molecular Biology from the University of Montpellier 2, France. He participated in the discovery of the metabotropic glutamate receptors and demonstrated synergism between various glutamate receptor subtypes for the activation of phospholipase A2. Subsequently, he worked as a post doctoral fellow at the Salk Institute where he cloned and characterized new mGlu receptor splice variants. In 1992, he set up a research team working on the structure function relationship of mGlu receptors in the CNRS laboratory in Montpellier. Currently, he heads the Molecular Pharmacology Department within the Institute of Functional Genomics, Montpellier, France where his research focuses on the molecular and cellular dynamics of GPCRs and has led to major new concepts in the GPCR field.

Von der hinteren Coverseite

G protein-coupled receptors (GPCRs) constitute the largest family of cell-surface receptors, with more than 800 members identified thus far in the human genome. They regulate the function of most cells in the body, and represent approximately 3% of the genes in the human genome. These receptors respond to a wide variety of structurally diverse ligands, ranging from small molecules, such as biogenic amines, nucleotides and ions, to lipids, peptides, proteins and even light. Ligands (agonists and antagonists) acting on GPCRs are important commonly used in drug therapy of numerous diseases, including cardiovascular and mental disorders, retinal degeneration, cancer, and AIDS. It is estimated that these receptors represent about one third of the actual identified targets of clinically used drugs. This book, which lies between the fields of chemical biology, molecular pharmacology and medicinal chemistry, is divided into three parts. The first part considers what receptor structures tell us about the mechanism of receptor activation. Part II focuses on receptor function. It discusses what the data from biophysical and mutational studies, and the analysis of the interactions of the receptor with ligands and regulator proteins, tell us about the process of signal transduction. The final part, on modelling and simulation, details what new insights on the link between structure and mechanism can be provided by theoretical studies and their implications in drug design. The various chapters present an update on the latest developments in GPCR structures and detailed structural changes linked to activation. They cover the latest news of the extraordinary complex function of these receptors, concentrating on the many aspects that are currently revolutionizing our current views of these proteins: receptor constitutive activity, receptor oligomerization, functional selectivity, biased agonism, multiple signalling pathways, multiple accessory proteins, functional cross talk and the mechanism of signal integration. This complex picture is tackled from complementary experimental and theoretical approaches, which represent a clear statement of our current knowledge of the GPCR complexity.

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G Protein–Coupled Receptors

From Structure to Function

By Jesús Giraldo Jean-Philippe Pin

The Royal Society of Chemistry

Copyright © 2011 The Royal Society of Chemistry
All rights reserved.
ISBN: 978-1-84973-183-6

Contents

Historical Perspective: From Receptors to G Protein-coupled Receptors to Seven Transmembrane Receptors: A Journey of Discovery Robert J. Lefkowitz, xxi, 
Section I G Protein-coupled Receptors: Membrane Proteins with Privileged Structures, 
Chapter 1 The Impact of G Protein-coupled Receptor (GPCR) Structures on Understanding Signal Transduction David T. Lodowski and Krzysztof Palczewski, 3, 
Chapter 2 Insights into GPCR Activation from NMR Spectroscopy Markus Eilers and Steven O. Smith, 28, 
Chapter 3 Signal Transfer from Receptor to G Protein: The Rhodopsin–Transducin Model O.G. Kisselev, J.H. Park, H.-W. Choe and O.P. Ernst, 54, 
Chapter 4 Peptide Hormone Recognition in Class B GPCRs: Role of the Extracellular Domain in Receptor Activation Christoph Parthier and Milton T. Stubbs, 75, 
Chapter 5 Oligomerization of G Protein-coupled Receptors: Insights from Fluorescent and Luminescent-based Methods Francisco Ciruela and Víctor Fernández-Dueñas, 90, 
Chapter 6 Ligand Regulation of GPCR Quaternary Structure L. Saenz del Burgo and G. Milligan, 111, 
Chapter 7 Lipid–Protein Interactions in G Protein Signal Transduction David J. López, Rafael Álvarez and Pablo V. Escribá, 153, 
Chapter 8 Use of Model Membranes to Study GPCR Signalling Units: Insights into Monomers and Oligomers D.M. Calinski, E. Edwald and R.K. Sunahara, 179, 
Section II G Protein-coupled Receptors: Multifaceted Functional Machines, 
Chapter 9 Kinetics and Mechanisms of GPCR Activation Manuela Ambrosio and Martin J. Lohse, 199, 
Chapter 10 Emerging Signalling Properties of the PTH Receptor Jean-Pierre Vilardaga, 217, 
Chapter 11 Metabotropic Glutamate Receptors: A Paradigm of Structural and Functional Receptor Complexity Jean-Philippe Pin, Julie Kniaze., Cyril Goudet, Thierry Durroux, Philippe Rondard and Laurent Prézeau, 232, 
Chapter 12 Crosstalk Between Receptors: Challenges of Distinguishing Upstream from Downstream Mechanisms Mahalaxmi Aburi, Marie-Laure Rives, Yang Han, Michaela Kralikova, Eneko Urizar, Hideaki Yano and Jonathan A. Javitch, 255, 
Chapter 13 Functional Crosstalk between Group I Metabotropic Glutamate Receptors and Ionotropic Glutamate Receptors Controls Synaptic Transmission Joel Bockaert, Laurent Fagni and Julie Perroy, 269, 
Chapter 14 Modulating Receptor Function through RAMPs Joseph J. Gingell and Debbie L. Hay, 284, 
Chapter 15 Activation of G Protein-Coupled Receptor (GPCR) Kinases by GPCRs John J. G. Tesmer, 297, 
Chapter 16 The Complex Role of G Protein-coupled Receptor Kinase 2 (GRK2) in Cell Signalling: Beyond GPCR Desensitization Federico Mayor Jr., Petronila Penela, Catalina Ribas and Cristina Murga, 316, 
Chapter 17 The Mechanics of Arrestin–Receptor Interaction: How GPCRs and Arrestins Talk to Each Other Vsevolod V. Gurevich and Eugenia V. Gurevich, 335, 
Section III Modelling G protein-coupled Receptor Structure and Function, 
Chapter 18 Structure-based Virtual Screening for Ligands of G Protein-coupled Receptors Stefano Costanzi, 359, 
Chapter 19 Probing the Activation Mechanism of Heptahelical Receptors: Experimental Validation of Molecular Dynamics Simulations P. Mukhopadhyay, T. Huber and T.P. Sakmar, 375, 
Chapter 20 Probing the Conformational Dynamics of GPCRs with Molecular Dynamics Simulation Ron O. Dror, Albert C. Pan, Daniel H. Arlow and David E. Shaw, 384, 
Chapter 21 Investigating Mechanisms of Ligand Recognition, Activation and Oligomerization in GPCRs Using Enhanced Molecular Dynamics Methods Jennifer M. Johnston and Marta Filizola, 401, 
Chapter 22 Functional Selectivity of Drugs for Seven Transmembrane Receptors: Biased Agonism and Antagonism Terry Kenakin, 429, 
Chapter 23 Functional Selectivity of G Protein-coupled Receptors: Bridging the Gap Between Monomeric and Dimeric Receptors X. Rovira and J. Giraldo, 446, 
Chapter 24 Using Microfluidics, Real-time Imaging and Mathematical Modelling to study GPCR Signalling Andreja Jovic, Shuichi Takayama and Jennifer J. Linderman, 469, 
Subject Index, 489,


CHAPTER 1

The Impact of G Protein-coupled Receptor (GPCR) Structures on Understanding Signal Transduction

DAVID T. LODOWSKI AND KRZYSZTOF PALCZEWSKI

Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106-4965, USA


1.1 Introduction

Recent advances in the structural study of G protein-coupled receptors (GPCRs) have significantly enriched our understanding of the process of G protein signalling, providing a structural framework to understand the huge volume of biochemical and biophysical studies on GPCRs performed and published over the past 50 years. Determination of X-ray crystal structures provides the most direct methodology for examining the structural aspects of GPCR signalling and careful analysis of these structures reveals mechanistic details shared by all GPCRs (Table 1.1).


1.2 Early Approaches to Analysing GPCR Structure

Prior to the determination of the rhodopsin structure, similarities were noted between the light responsive photopigment, bacteriorhodopsin, and purified bovine rhodopsin, including their Schiff base linkage of chromophore, photoactivation and seven-transmembrane architecture (Figure 1.1A). After structure determination of bacteriorhodopsin via electron crystallography, (reviewed in ref. 18), it was assumed that these two proteins shared a similar architecture. Protein and DNA sequencing of rhodopsin and the β2- adrenergic receptor, coupled with hydropat hy plots, allowed the construction of two-dimensional (2-D) topology models (Figure 1.1B and 1.1C). Further clarification provided by electron crystallographic studies of 2-D crystals of bovine (Figure 1.1D) and invertebrate rhodopsin suggested that the arrangement of helices in bacteriorhodopsin versus rhodopsin and other GPCRs were distinct. These studies also improved predictions of the helical arrangement within the transmembrane bundle (Figure 1.1E). Mutagenesis and biochemical studies allowed location assignments of disulfide bonds, palmitoylation, and phosphorylation sites as well as further clarification of the border between loop and transmembrane regions (reviewed in ref. 42–46) (Figure 1.1F).


1.3 The Crystal Structure of Rhodopsin

While several laboratories were able to obtain crystals of rhodopsin, these studies did not result in the determination of a crystal structure. A postdoctoral fellow and a technician in our laboratory, Dr. Tetsuji Okada and Preston Van Hoosier, were able to improve the purification of rhodopsin from a very high quality preparation of bovine rod outer segment membranes. This provided homogenous bovine rhodopsin at the purity, quantity and concentration necessary to enable growth of diffraction quality crystals. These crystals led to the determination of the first crystal structure of rhodopsin and subsequent rhodopsin structures extended the resolution to 2.2 Å, facilitating subsequent structural studies of additional GPCRs obtained by similar purification methods, as well as those obtained by an alternative purification method. These structures supplied the first true atomistic view of any GPCR, fully defining...

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Verlag
Royal Society of Chemistry
Erscheinungsdatum
2011
Sprache
Englisch
ISBN 10 
1849731837
ISBN 13 
9781849731836
Einband
Gebundene Ausgabe
Anzahl der Seiten
511
Herausgeber
Giraldo Jesus, Pin Jean-philippe
Kontakt zum Hersteller
Nicht verfügbar
Verantwortliche Person
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