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GPCR Molecular Pharmacology and Drug Targeting: Shifting Paradigms and New Directions / Edition 1

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G protein-coupled receptors (GPCRs) are a large protein family of transmembrane receptors vital in dictating cellular responses. GPCRs are involved in many diseases, but are also the target of around half of all modern medicinal drugs.  Shifting Paradigms in G Protein Coupled Receptors takes a look at the way GPCRs are examined today, how they react, how their mutations lead to disease, and the many ways in which they can be screened for compounds that modulate them. Chemists, pharmacologists, and biologists will find essential information in this comprehensive reference.

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Editorial Reviews

From the Publisher
"Additionally, the presentation of the fundamental concepts of GPCR biology by the authors, who are recognized experts in the GPCR field, is likely to be appreciated by students of pharmacology. . . This is a unique resource for navigating the field of GPCR research." (Doody's, 23 September 2011)

"The first emerge as promising therapeutic targets and, as understanding of their pharmacology advances, new treatments for various diseases can be uncovered." (ChemMedChem, 1 February 2011)

Doody's Review Service
Reviewer: Rachel R Chennault, PhD (American College of Clinical Pharmacy)
Description: This book examines the various properties and functions of G protein-coupled receptors (GPCRs) that make them useful targets for therapeutic intervention and addresses advances in screening approaches to identify potential drug candidates that modulate cellular events upon activation of G protein-coupled receptors.
Purpose: Because our understanding of how G protein-coupled receptors mediate cellular responses is constantly evolving, the purpose of this book is to update readers on recent advances in the field, particularly with respect to the utility of GPCRs as a target class in molecular pharmacology. This book details recent developments in GPCR research and lays the necessary foundation upon which the discovery of new drug products involving GPCRs may proceed.
Audience: The intended audience of scientists includes chemists, pharmacologists, and biologists in both the academic and industrial sectors. Additionally, the presentation of the fundamental concepts of GPCR biology by the authors, who are recognized experts in the GPCR field, is likely to be appreciated by students of pharmacology.
Features: The book begins with a historical perspective on the concept of drug receptors, detailing the processes by which new theories about GPCR functions evolved. Subsequent chapters discuss the appropriateness of both traditional and high-throughput screening techniques to discover modulators of G protein-coupled receptors as a means to develop novel therapeutics. Color illustrations pertaining to these methods and GPCR function are particularly instructive.
Assessment: This is a unique resource for navigating the field of GPCR research. Although other books nay have detailed descriptions of GPCR function, screening methodology, and pharmacology (e.g., G Protein-coupled Receptors: Molecular Pharmacology, Vauquelin and von Mentzer (John Wiley & Sons, 2007), this one devotes an entire chapter to examining hereditary human diseases that arise by GPCR inactivating mutations, expanding the context of GPCR research into potential therapies involving pharmacological chaperones.
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Product Details

  • ISBN-13: 9780470307786
  • Publisher: Wiley
  • Publication date: 8/9/2010
  • Edition number: 1
  • Pages: 536
  • Product dimensions: 6.30 (w) x 9.30 (h) x 1.40 (d)

Meet the Author

Annette Gilchrist, PhD, is Assistant Professor of Pharmaceutical Sciences at Midwestern Univeristy’s Chicago of Pharmacy, and Adjunct Professor at Northwestern University in the Department of Molecular Pharmacology and Biological Chemistry. Previously, she cofounded and was chief scientific officer for Caden Biosciences, and cofounded and was president of Cue BIOtech, companies committed to GPCR discovery efforts. A life sciences industry consultant and regular speaker at ACS, SBS, DIA, BIO, and CHI conferences, she has twenty-four peer-reviewed publications and four issued patents.

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Table of Contents



1 The Evolution of Receptors: From On-Off Switches to Microprocessors Terry Kenakin Kenakin, Terry 1

1.1 Introduction 1

1.2 The Receptor as an On-Off Switch 1

1.3 Historical Background and Classical Receptor Theory 2

1.4 The Operational Model of Drug Action 7

1.5 Receptor Antagonism 8

1.6 Specific Models of GPCRs (7TM Receptors) 11

1.7 The Receptor as Microprocessor: Ternary Complex Models 13

1.8 Receptors as Basic Drug Recognition Units 17

1.9 Receptor Structure 19

1.10 Future Considerations 19

References 22

2 The Evolving Pharmacology of GPCRs Stephen J. Hill Hill, Stephen J. 27

2.1 Agonists, Neutral Antagonists, and Inverse Agonists 27

2.1.1 Affinity and Efficacy 27

2.1.2 Pharmacological Models of Agonism, Antagonism, and Inverse Agonism 32

2.2 LDTRS/Protean Agonism 34

2.3 Molecular Mechanisms of GPCR Ligand Binding 35

2.3.1 Rhodopsin-Like Receptor Binding Sites 35

2.3.2 Ligand Recognition in Class C Receptors 38

2.3.3 Molecular Mechanisms of Rhodopsin-Like Receptor Activation 39

2.4 Two GPCR Ligands Binding at Once--Concept of Allosterism 40

2.4.1 Classes of Allosteric Modulators 40

2.4.2 Pharmacological Models of Allosteric Interactions 41

2.4.3 Advantages of Allosteric Ligands 43

2.5 GPCR Dimerization 44

2.5.1 Dimerization is Essential for Class C Receptor Function 44

2.5.2 Is Dimerization Required for Class A GPCR Activation? 46

2.5.3 Influence of Receptor Dimers on Binding Studies 47

2.5.4 GPCR Heterodimerization 48

2.6 Future Perspectives 49

Acknwowledgments 50

References 50

3 The Emergence of Allosteric Modulators for G Protein-Coupled Receptors Arthur Christopoulos Christopoulos, Arthur 61

3.1 Introduction 61

3.2 Foundations of Allosteric Receptor Theory 62

3.3 Models for Understanding the Effects of Allosteric Modulators 63

3.4 Types of Allosteric Modulators and Their Properties 65

3.5 Detection and Quantification of Allosteric Interactions 68

3.5.1 Radioligand Binding Assays 68

3.5.2 Functional Assays 70

3.6 Some Examples of GPCR Allosteric Modulators 73

3.6.1 Small Molecule Allosteric Modulators 73

3.6.2 Proteins as Allosteric Modulators 78

3.7 Concluding Remarks 80

References 81

4 Receptor-Mediated G Protein Activation: How, How Many, and Where? Michael Freissmuth Freissmuth, Michael 88

4.1 The Mechanical Problem---Three Different Solutions 89

4.1.1 The Lever-Arm Model 91

4.1.2 The "Gear-Shift" Model 91

4.1.3 The "C-Terminal Latch" Model 93

4.1.4 Are the Three Models Mutually Exclusive? 94

4.2 Receptor Monomers-Dimers-Oligomers: One Size Fits All? 95

4.2.1 Evidence for GPCR Dimers 96

4.2.2 GPCR Dimers Are Not Universally Required as Prerequisites for G Protein Activation 96

4.2.3 Dimers May Allow for Conformational Switches Underlying Receptor Cross-Talk and Other Forms of Allosterism 99

4.3 Corrals, Fences, Rafts---Are There Privileged Places for GPCR Activation? 100

4.3.1 The Actin Cytoskeleton Confines GPCRs by Several Mechanisms 100

4.3.2 Cholesterol-Rich Domains and Lipid Rafts 103

Acknowledgments 106

References 106

5 Molecular Pharmacology of Frizzleds---with Implications for Possible Therapy Gunnar Schulte Schulte, Gunnar 113

5.1 Introduction 113

5.2 Frizzleds as WNT Receptors 113

5.2.1 Frizzleds---The Discovery 113

5.2.2 The Frizzled Family 114

5.2.3 Frizzled Ligands 116

5.2.4 WNT-Frizzled Interactions 116

5.2.5 Intracellular Posttranslational Modifications 117

5.3 Frizzled Signaling 120

5.3.1 β-Catenin-Dependent Signaling 122

5.3.2 β-Catenin-Independent Signaling 122

5.3.3 Intracellular Scaffolds (DVL and β-arrestin) 123

5.3.4 Evidence for G Protein Coupling of FZDs 125

5.3.5 Unconventional Signaling Modes 126

5.4 Frizzleds---Physiology and Possible Therapy 127

5.4.1 Frizzleds in Physiology 127

5.4.2 Therapeutic Potential 128

5.4.3 Attacking WNT-FZD Interface? 128

5.4.4 Anti-DVL Drugs 129

5.4.5 WNTs as Drugs 129

5.4.6 Future Directions 130

Acknowledgments 130

References 130

6 Secretin Receptor Dimerization: A Possible Functionally Important Paradigm for Family B G Protein-Coupled Receptors Laurence J. Miller Miller, Laurence J. 138

6.1 Methodological Approaches to GPCR Oligomerization 139

6.2 Structural Themes for GPCR Oligomerization 141

6.3 Functional Effects of GPCR Oligomerization 150

6.4 Secretin Receptor Oligomerization 151

References 153

7 Past and Future Strategies for GPCR Deorphanization Ralf Jockers Jockers, Ralf 165

7.1 Introduction 165

7.2 Current Strategies to Identify the Ligand and Function of Orphan 7TM Proteins 168

7.2.1 Reverse Pharmacology 168

7.2.2 Orphan Receptor Strategy 168

7.2.3 Use of Sequence Homology, Cross Genome Phylogenetic Analysis, and Chemogenomics to Predict Candidate Ligands 168

7.2.4 Determination of the Expression Pattern and the Phenotype of Knockout Mice of Orphan 7TM Proteins 170

7.3 Functional Assays for Deorphanization 170

7.3.1 Classical Assays of GPCR Deorphanization 173

7.3.2 Recent Assays in GPCR Deorphanization 174

7.4 Future Directions and New Concepts 176

7.5 Controversial Issues 179

Acknowledgments 181

References 181

8 High-Throughput GPCR Screening Technologies and the Emerging Importance of the Cell Phenotype Richard M. Eglen Eglen, Richard M. 191

8.1 Introduction 191

8.2 How Are GPCR Drugs Discovered? 192

8.3 GPCR Dependence on G Proteins 193

8.4 Technologies for GPCR Compound Screening and Drug Discovery 195

8.4.1 Cell-Free Assays 195

8.4.2 Cell-Based Assays 195

8.4.3 Ca++ Transients for GPCR HTS 196

8.4.4 Reporter Assays for GPCR HTS 198

8.4.5 Universal HTS Assays for GPCRs? 198

8.5 Importance of Target Cells in GPCR HTS Assays 199

8.6 Summary 203

References 204

9 Are "Traditional" Biochemical Techniques Out of Fashion in the New Era of GPCR Pharmacology? Maria Rosa Mazzoni Mazzoni, Maria Rosa 209

9.1 Overview 209

9.2 Receptor Binding Assays 210

9.3 Methods for Measurement of cAMP 216

9.3.1 Assessments of Adenylyl Cyclase Activity: Methods Using Labeled ATP 216

9.3.2 Methods Using Nonlabeled ATP 218

9.4 Conclusions 223

References 223

10 Fluorescence and Resonance Energy Transfer Shine New Light on GPCR Function Moritz Bunemann Bunemann, Moritz 226

10.1 Overview 226

10.2 Introduction 226

10.3 Labeling GPCRs with Fluorescent Tags 227

10.3.1 Tagging GPCRs with Fluorescent Proteins 227

10.3.2 Labeling of GPCRs with Fluorescent Dyes 228

10.4 Detection of Fluorescence and Bioluminescence 231

10.5 Fluorescence-Based Assays to Study Receptor Localization, Trafficking and Receptor Function 232

10.5.1 How to Monitor Receptor Function by Means of Fluorescence Microscopy 233

10.6 Resonance Energy Transfer, a Tool to Get New Insights into GPCR Function 234

10.6.1 BRET 234

10.6.2 FRET 234

10.6.3 Comparison of BRET and FRET 235

10.7 Analysis of Steady-State Protein-Protein Interaction by Means of RET 236

10.8 Kinetic Analysis of Protein-Protein Interactions by Means of FRET 237

10.8.1 G Protein Activity Measured by FRET 238

10.8.2 Receptor-G Protein Interaction Studied by RET 239

10.8.3 Kinetics of Receptor-G Protein Interactions 240

10.8.4 Receptor-β-arrestin Interaction Detected by RET 242

10.9 Detection of Receptor Function by Fluorescence Resonance Energy 243

10.9.1 Partial Agonism Detected on the Level of the Receptor 245

10.9.2 Inverse Agonism Detected at the Level of the Receptor 246

References 247

11 Integration of Label-Free Detection Methods in GPCR Drug Discovery John Gatfield Gatfield, John 252

11.1 Overview 252

11.2 Introduction 253

11.3 Label-Free Technologies---Past and Present 255

11.3.1 Automated Microscopes and Microbalances 256

11.3.2 Microphysiometry 257

11.3.3 Impedance/RWG 259

11.4 Discussion 270

Acknowledgments 272

References 272

12 Screening for Allosteric Modulators of G Protein-Coupled Receptors Christopher Langmead Langmead, Christopher 276

12.1 Introduction 276

12.2 The Allosteric Ternary Complex Model, Radioligand Binding, and Affinity 278

12.3 Beyond Affinity---Functional Assays, Efficacy, and Allosteric Agonism 281

12.4 Allosteric Modulator Titration Curves 286

12.5 The Impact of Functional Assay Format on Allosteric Modulator Screening 289

12.6 Taking Advantage of Structural Understanding of Allosteric Binding Sites 293

12.7 Summary and Future Directions 294

References 295

13 Ultra-High-Throughput Screening Assays for GPCRs Priya Kunapuli Kunapuli, Priya 300

13.1 Introduction 300

13.2 Assay Types for GPCRs in uHTS 303

13.2.1 Radioligand Displacement Assays 303

13.2.2 Functional Assays 305

13.3 Summary 317

Acknowledgments 319

References 319

14 New Techniques to Express and Crystallize G Protein-Coupled Receptors Fiona H. Marshall Marshall, Fiona H. 324

14.1 Introduction 324

14.2 Key Problems Limiting Production of 3D GPCR Structures 327

14.3 History of GPCR Structures 329

14.3.1 Early Studies on Rhodopsin 329

14.3.2 Higher Resolution Structures of Bovine Rhodopsin Using X-Ray Crystallography 333

14.3.3 Squid Rhodopsin 336

14.3.4 Activated Opsin and Binding to G Proteins 337

14.3.5 Rhodopsin as a Model for Other GPCRs 340

14.4 The Search for Other GPCR Structures 340

14.4.1 Expression of Recombinant Receptors 340

14.4.2 Factors Influencing GPCR Overexpression 349

14.4.3 Summary 350

14.5 Protein Purification and Solubilization 351

14.5.1 Choice of Detergents for Structural Studies 355

14.5.2 Crystallization Chaperones 356

14.6 In Cubo Crystallization 358

14.7 Engineering Receptor Stability 361

14.8 Structures of the B2AR 365

14.9 The Adenosine A2a Receptor 369

14.10 Conclusions and Future Developments 371

Acknowledgments 371

References 371

15 Structure and Modeling of GPCRs: Implications for Drug Discovery Ruben Abagyan Abagyan, Ruben 385

15.1 Introduction 385

15.2 High-Resolution GPCR Modeling 389

15.2.1 From Electron Density to a Full Atom Model Suitable for Drug Discovery: Refinement of Existing Crystal Structures 389

15.2.2 Ligand-Guided Modeling of Binding Pocket Conformation 392

15.2.3 Coupling LGM and TM Domain Motions to Capture Binding Site Conformational Changes Necessary for Agonist Recognition 397

15.2.4 VLS with High-Resolution Models: Antagonist/Agonist Selectivity 398

15.3 Constructing and Evaluating Homology Models of Other Receptor Types 402

15.3.1 A Note on De Novo Methods 402

15.3.2 Criteria for Homology Model Template Selection 403

15.3.3 Structure and Modeling of Loop Regions 409

15.3.4 GPCR Model Validation and Evaluation 411

15.3.5 Ligand Subtype Selectivity in GPCR Models 413

15.4 Modeling GPCR Functional Features---Analysis of Activation and Signaling 415

15.4.1 Activation-Related Conformational Changes in GPCRs 416

15.4.2 Macromolecular Complexes of GPCRs 417

15.5 Beyond Class A: Modeling of Other GPCR Families 418

15.5.1 Modeling Secretin (Class B) Family GPCRs 418

15.5.2 Glutamate/Class C 420

15.5.3 Orphan GPCRs 421

15.6 Summary and Conclusions 422

Acknowledgments 422

References 422

16 X-Ray Structure Developments for GPCR Drug Targets Sidney W. Topiol Topiol, Sidney W. 434

16.1 Overview 434

16.2 Introduction 434

16.3 Class A GPCRs 438

16.3.1 Sequence Homology 438

16.3.2 Stabilization of X-Ray Structures 438

16.3.3 The Overall Topology of the 7TM Region 440

16.3.4 The Binding Site 441

16.3.5 The ECL2 443

16.3.6 The Toggle Switch 443

16.3.7 The Ionic Lock 444

16.3.8 The ICL3 Region and Activation 445

16.3.9 Computational Chemistry Successes and Limitations 447

16.4 Class C GPCRs 449

16.4.1 Global Architecture 449

16.4.2 The VFT Domain 450

16.4.3 The C-rich Domain 451

16.4.4 Computational Studies 452

16.5 Conclusions 452

References 453

17 Pharmacological Chaperones: Potential for the Treatment of Hereditary Diseases Caused by Mutations in G Protein-Coupled Receptors Michel Bouvier Bouvier, Michel 460

17.1 Overview 460

17.2 Introduction 461

17.3 NDI and the V2R 464

17.4 RP and the Rhodopsin Receptor 470

17.5 IHH and the Gonadotropin-Releasing Hormone Receptor 476

17.6 Other Human Diseases Caused by Inactivating Mutations in GPCRs 479

17.6.1 Class A GPCRs 479

17.6.2 Class B GPCRs 482

17.6.3 Class C GPCRs 483

17.6.4 Family Frizzled/Smoothened GPCRs 484

17.7 Considerations for the Therapeutic Use of Pharmacological Chaperones 485

17.7.1 Pharmacogenetics 485

17.7.2 Dominant-Negative Effects 486

17.7.3 Function of Rescued GPCRs with Missense Mutations 488

17.7.4 Biophysical Requirements of Pharmacological Chaperones 488

17.7.5 Safety 490

17.8 Concluding Remarks 490

Acknowledgments 491

References 491

Index 511

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