GPCR Molecular Pharmacology and Drug Targeting (eBook, PDF)
Shifting Paradigms and New Directions
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GPCR Molecular Pharmacology and Drug Targeting (eBook, PDF)
Shifting Paradigms and New Directions
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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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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.
Produktdetails
- Produktdetails
- Verlag: John Wiley & Sons
- Seitenzahl: 544
- Erscheinungstermin: 8. Juni 2010
- Englisch
- ISBN-13: 9780470627310
- Artikelnr.: 37297853
- Verlag: John Wiley & Sons
- Seitenzahl: 544
- Erscheinungstermin: 8. Juni 2010
- Englisch
- ISBN-13: 9780470627310
- Artikelnr.: 37297853
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.
Preface. Contributors. 1. The Evolution of Receptors: From On-Off Switches
to Microprocessors (Terry Kenakin). 1.1. Introduction. 1.2. The Receptor as
an On-Off Switch. 1.3. Historical Background and Classical Receptor Theory.
1.4. The Operational Model of Drug Action. 1.5. Receptor Antagonism. 1.6.
Specific Models of GPCRs (7TM Receptors). 1.7. The Receptor as
Microprocessor: Ternary Complex Models. 1.8. Receptors as Basic Drug
Recognition Units. 1.9. Receptor Structure. 1.10. Future Considerations.
References. 2. The Evolving Pharmacology of GPCRs 27 (Lauren T. May,
Nicholas D. Holliday, and Stephen J. Hill). 2.1. Agonists, Neutral
Antagonists, and Inverse Agonists. 2.2. LDTRS/Protean Agonism. 2.3.
Molecular Mechanisms of GPCR Ligand Binding. 2.4. Two GPCR Ligands Binding
at Once--Concept of Allosterism. 2.5. GPCR Dimerization. 2.6. Future
Perspectives. Acknowledgments. References. 3. The Emergence of Allosteric
Modulators for G Protein-Coupled Receptors (Karen J. Gregory, Celine
Valant, John Simms, Patrick M. Sexton, and Arthur Christopoulos). 3.1.
Introduction. 3.2. Foundations of Allosteric Receptor Theory. 3.3. Models
for Understanding the Effects of Allosteric Modulators. 3.4. Types of
Allosteric Modulators and Their Properties. 3.5. Detection and
Quantification of Allosteric Interactions. 3.6. Some Examples of GPCR
Allosteric Modulators. 3.7. Concluding Remarks. References. 4.
Receptor-Mediated G Protein Activation: How, How Many, and Where? (Ingrid
Gsandtner, Christian W. Gruber, and Michael Freissmuth). 4.1. The
Mechanical Problem--Three Different Solutions. 4.2. Receptor
Monomers-Dimers-Oligomers: One Size Fits All? 4.3. Corrals, Fences,
Rafts--Are There Privileged Places for GPCR Activation? Acknowledgments.
References. 5. Molecular Pharmacology of Frizzleds--with Implications for
Possible Therapy (Gunnar Schulte). 5.1. Introduction. 5.2. Frizzleds as WNT
Receptors. 5.3. Frizzled Signaling 120. 5.4. Frizzleds--Physiology and
Possible Therapy. Acknowledgments. References. 6. Secretin Receptor
Dimerization: A Possible Functionally Important Paradigm for Family B G
Protein-Coupled Receptors (Kaleeckal G. Harikumar, Maoqing Dong, and
Laurence J. Miller). 6.1. Methodological Approaches to GPCR
Oligomerization. 6.2. Structural Themes for GPCR Oligomerization. 6.3.
Functional Effects of GPCR Oligomerization. 6.4. Secretin Receptor
Oligomerization. References. 7. Past and Future Strategies for GPCR
Deorphanization (Angélique Levoye, Nathalie Clement, Elodie Tenconi and
Ralf Jockers). 7.1. Introduction. 7.2. Current Strategies to Identify the
Ligand and Function of Orphan 7TM Proteins. 7.3. Functional Assays for
Deorphanization. 7.4. Future Directions and New Concepts. 7.5.
Controversial Issues. Acknowledgments. References. 8. High-Throughput GPCR
Screening Technologies and the Emerging Importance of the Cell Phenotype
(Terry Reisine and Richard M. Eglen). 8.1. Introduction. 8.2. How Are GPCR
Drugs Discovered? 8.3. GPCR Dependence on G Proteins. 8.4. Technologies for
GPCR Compound Screening and Drug Discovery. 8.5. Importance of Target Cells
in GPCR HTS Assays. 8.6. Summary. References. 9. Are "Traditional"
Biochemical Techniques Out of Fashion in the New Era of GPCR Pharmacology?
(Maria Teresa Dell'anno and Maria Rosa Mazzoni). 9.1. Overview. 9.2.
Receptor Binding Assays. 9.3. Methods for Measurement of cAMP. 9.4.
Conclusions. References. 10. Fluorescence and Resonance Energy Transfer
Shine New Light on GPCR Function (Carsten Hoffmann and Moritz Bünemann).
10.1. Overview. 10.2. Introduction. 10.3. Labeling GPCRs with Fluorescent
Tags. 10.4. Detection of Fluorescence and Bioluminescence. 10.5.
Fluorescence-Based Assays to Study Receptor Localization, Trafficking and
Receptor Function. 10.6. Resonance Energy Transfer, a Tool to Get New
Insights into GPCR Function. 10.7. Analysis of Steady-State Protein-Protein
Interaction by Means of RET. 10.8. Kinetic Analysis of Protein-Protein
Interactions by Means of FRET. 10.9. Detection of Receptor Function by
Fluorescence Resonance Energy. References. 11. Integration of Label-Free
Detection Methods in GPCR Drug Discovery (Oliver Nayler, Magdalena
Birker-Robaczewska, and John Gatfield). 11.1. Overview. 11.2. Introduction.
11.3. Label-Free Technologies--Past and Present. 11.4. Discussion.
Acknowledgments. References. 12. Screening for Allosteric Modulators of G
Protein-Coupled Receptors (Christopher Langmead). 12.1. Introduction. 12.2.
The Allosteric Ternary Complex Model, Radioligand Binding, and Affinity.
12.3. Beyond Affinity--Functional Assays, Efficacy, and Allosteric Agonism.
12.4. Allosteric Modulator Titration Curves. 12.5. The Impact of Functional
Assay Format on Allosteric Modulator Screening. 12.6. Taking Advantage of
Structural Understanding of Allosteric Binding Sites. 12.7. Summary and
Future Directions. References. 13. Ultra-High-Throughput Screening Assays
for GPCRs (Priya Kunapuli). 13.1. Introduction. 13.2. Assay Types for GPCRs
in uHTS. 13.3. Summary. Acknowledgments. References. 14. New Techniques to
Express and Crystallize G Protein-Coupled Receptors (James C. Errey and
Fiona H. Marshall). 14.1. Introduction. 14.2. Key Problems Limiting
Production of 3D GPCR Structures. 14.3. History of GPCR Structures. 14.4.
The Search for Other GPCR Structures. 14.5. Protein Purification and
Solubilization. 14.6. In Cubo Crystallization. 14.7. Engineering Receptor
Stability. 14.8. Structures of the â2AR. 14.9. The Adenosine A2a Receptor.
14.10. Conclusions and Future Developments. Acknowledgments. References.
15. Structure and Modeling of GPCRs: Implications for Drug Discovery
(Kimberly A. Reynolds, Vsevolod Katritch, and Ruben Abagyan). 15.1.
Introduction. 15.2. High-Resolution GPCR Modeling. 15.3. Constructing and
Evaluating Homology Models of Other Receptor Types. 15.4. Modeling GPCR
Functional Features--Analysis of Activation and Signaling. 15.5. Beyond
Class A: Modeling of Other GPCR Families. 15.6. Summary and Conclusions.
Acknowledgments. References. 16. X-Ray Structure Developments for GPCR Drug
Targets (Michael Sabio and Sidney W. Topiol). 16.1. Overview. 16.2.
Introduction. 16.3. Class A GPCRs. 16.4. Class C GPCRs. 16.5. Conclusions.
References. 17. Pharmacological Chaperones: Potential for the Treatment of
Hereditary Diseases Caused by Mutations in G Protein-Coupled Receptors
(Kenneth J. Valenzano, Elfrida R. Benjamin,Patricia René, and Michel
Bouvier). 17.1. Overview. 17.2. Introduction. 17.3. NDI and the V2R. 17.4.
RP and the Rhodopsin Receptor. 17.5. IHH and the Gonadotropin-Releasing
Hormone Receptor. 17.6. Other Human Diseases Caused by Inactivating
Mutations in GPCRs. 17.7. Considerations for the Therapeutic Use of
Pharmacological Chaperones. 17.8. Concluding Remarks. Acknowledgments.
References. Index.
to Microprocessors (Terry Kenakin). 1.1. Introduction. 1.2. The Receptor as
an On-Off Switch. 1.3. Historical Background and Classical Receptor Theory.
1.4. The Operational Model of Drug Action. 1.5. Receptor Antagonism. 1.6.
Specific Models of GPCRs (7TM Receptors). 1.7. The Receptor as
Microprocessor: Ternary Complex Models. 1.8. Receptors as Basic Drug
Recognition Units. 1.9. Receptor Structure. 1.10. Future Considerations.
References. 2. The Evolving Pharmacology of GPCRs 27 (Lauren T. May,
Nicholas D. Holliday, and Stephen J. Hill). 2.1. Agonists, Neutral
Antagonists, and Inverse Agonists. 2.2. LDTRS/Protean Agonism. 2.3.
Molecular Mechanisms of GPCR Ligand Binding. 2.4. Two GPCR Ligands Binding
at Once--Concept of Allosterism. 2.5. GPCR Dimerization. 2.6. Future
Perspectives. Acknowledgments. References. 3. The Emergence of Allosteric
Modulators for G Protein-Coupled Receptors (Karen J. Gregory, Celine
Valant, John Simms, Patrick M. Sexton, and Arthur Christopoulos). 3.1.
Introduction. 3.2. Foundations of Allosteric Receptor Theory. 3.3. Models
for Understanding the Effects of Allosteric Modulators. 3.4. Types of
Allosteric Modulators and Their Properties. 3.5. Detection and
Quantification of Allosteric Interactions. 3.6. Some Examples of GPCR
Allosteric Modulators. 3.7. Concluding Remarks. References. 4.
Receptor-Mediated G Protein Activation: How, How Many, and Where? (Ingrid
Gsandtner, Christian W. Gruber, and Michael Freissmuth). 4.1. The
Mechanical Problem--Three Different Solutions. 4.2. Receptor
Monomers-Dimers-Oligomers: One Size Fits All? 4.3. Corrals, Fences,
Rafts--Are There Privileged Places for GPCR Activation? Acknowledgments.
References. 5. Molecular Pharmacology of Frizzleds--with Implications for
Possible Therapy (Gunnar Schulte). 5.1. Introduction. 5.2. Frizzleds as WNT
Receptors. 5.3. Frizzled Signaling 120. 5.4. Frizzleds--Physiology and
Possible Therapy. Acknowledgments. References. 6. Secretin Receptor
Dimerization: A Possible Functionally Important Paradigm for Family B G
Protein-Coupled Receptors (Kaleeckal G. Harikumar, Maoqing Dong, and
Laurence J. Miller). 6.1. Methodological Approaches to GPCR
Oligomerization. 6.2. Structural Themes for GPCR Oligomerization. 6.3.
Functional Effects of GPCR Oligomerization. 6.4. Secretin Receptor
Oligomerization. References. 7. Past and Future Strategies for GPCR
Deorphanization (Angélique Levoye, Nathalie Clement, Elodie Tenconi and
Ralf Jockers). 7.1. Introduction. 7.2. Current Strategies to Identify the
Ligand and Function of Orphan 7TM Proteins. 7.3. Functional Assays for
Deorphanization. 7.4. Future Directions and New Concepts. 7.5.
Controversial Issues. Acknowledgments. References. 8. High-Throughput GPCR
Screening Technologies and the Emerging Importance of the Cell Phenotype
(Terry Reisine and Richard M. Eglen). 8.1. Introduction. 8.2. How Are GPCR
Drugs Discovered? 8.3. GPCR Dependence on G Proteins. 8.4. Technologies for
GPCR Compound Screening and Drug Discovery. 8.5. Importance of Target Cells
in GPCR HTS Assays. 8.6. Summary. References. 9. Are "Traditional"
Biochemical Techniques Out of Fashion in the New Era of GPCR Pharmacology?
(Maria Teresa Dell'anno and Maria Rosa Mazzoni). 9.1. Overview. 9.2.
Receptor Binding Assays. 9.3. Methods for Measurement of cAMP. 9.4.
Conclusions. References. 10. Fluorescence and Resonance Energy Transfer
Shine New Light on GPCR Function (Carsten Hoffmann and Moritz Bünemann).
10.1. Overview. 10.2. Introduction. 10.3. Labeling GPCRs with Fluorescent
Tags. 10.4. Detection of Fluorescence and Bioluminescence. 10.5.
Fluorescence-Based Assays to Study Receptor Localization, Trafficking and
Receptor Function. 10.6. Resonance Energy Transfer, a Tool to Get New
Insights into GPCR Function. 10.7. Analysis of Steady-State Protein-Protein
Interaction by Means of RET. 10.8. Kinetic Analysis of Protein-Protein
Interactions by Means of FRET. 10.9. Detection of Receptor Function by
Fluorescence Resonance Energy. References. 11. Integration of Label-Free
Detection Methods in GPCR Drug Discovery (Oliver Nayler, Magdalena
Birker-Robaczewska, and John Gatfield). 11.1. Overview. 11.2. Introduction.
11.3. Label-Free Technologies--Past and Present. 11.4. Discussion.
Acknowledgments. References. 12. Screening for Allosteric Modulators of G
Protein-Coupled Receptors (Christopher Langmead). 12.1. Introduction. 12.2.
The Allosteric Ternary Complex Model, Radioligand Binding, and Affinity.
12.3. Beyond Affinity--Functional Assays, Efficacy, and Allosteric Agonism.
12.4. Allosteric Modulator Titration Curves. 12.5. The Impact of Functional
Assay Format on Allosteric Modulator Screening. 12.6. Taking Advantage of
Structural Understanding of Allosteric Binding Sites. 12.7. Summary and
Future Directions. References. 13. Ultra-High-Throughput Screening Assays
for GPCRs (Priya Kunapuli). 13.1. Introduction. 13.2. Assay Types for GPCRs
in uHTS. 13.3. Summary. Acknowledgments. References. 14. New Techniques to
Express and Crystallize G Protein-Coupled Receptors (James C. Errey and
Fiona H. Marshall). 14.1. Introduction. 14.2. Key Problems Limiting
Production of 3D GPCR Structures. 14.3. History of GPCR Structures. 14.4.
The Search for Other GPCR Structures. 14.5. Protein Purification and
Solubilization. 14.6. In Cubo Crystallization. 14.7. Engineering Receptor
Stability. 14.8. Structures of the â2AR. 14.9. The Adenosine A2a Receptor.
14.10. Conclusions and Future Developments. Acknowledgments. References.
15. Structure and Modeling of GPCRs: Implications for Drug Discovery
(Kimberly A. Reynolds, Vsevolod Katritch, and Ruben Abagyan). 15.1.
Introduction. 15.2. High-Resolution GPCR Modeling. 15.3. Constructing and
Evaluating Homology Models of Other Receptor Types. 15.4. Modeling GPCR
Functional Features--Analysis of Activation and Signaling. 15.5. Beyond
Class A: Modeling of Other GPCR Families. 15.6. Summary and Conclusions.
Acknowledgments. References. 16. X-Ray Structure Developments for GPCR Drug
Targets (Michael Sabio and Sidney W. Topiol). 16.1. Overview. 16.2.
Introduction. 16.3. Class A GPCRs. 16.4. Class C GPCRs. 16.5. Conclusions.
References. 17. Pharmacological Chaperones: Potential for the Treatment of
Hereditary Diseases Caused by Mutations in G Protein-Coupled Receptors
(Kenneth J. Valenzano, Elfrida R. Benjamin,Patricia René, and Michel
Bouvier). 17.1. Overview. 17.2. Introduction. 17.3. NDI and the V2R. 17.4.
RP and the Rhodopsin Receptor. 17.5. IHH and the Gonadotropin-Releasing
Hormone Receptor. 17.6. Other Human Diseases Caused by Inactivating
Mutations in GPCRs. 17.7. Considerations for the Therapeutic Use of
Pharmacological Chaperones. 17.8. Concluding Remarks. Acknowledgments.
References. Index.
Preface. Contributors. 1. The Evolution of Receptors: From On-Off Switches
to Microprocessors (Terry Kenakin). 1.1. Introduction. 1.2. The Receptor as
an On-Off Switch. 1.3. Historical Background and Classical Receptor Theory.
1.4. The Operational Model of Drug Action. 1.5. Receptor Antagonism. 1.6.
Specific Models of GPCRs (7TM Receptors). 1.7. The Receptor as
Microprocessor: Ternary Complex Models. 1.8. Receptors as Basic Drug
Recognition Units. 1.9. Receptor Structure. 1.10. Future Considerations.
References. 2. The Evolving Pharmacology of GPCRs 27 (Lauren T. May,
Nicholas D. Holliday, and Stephen J. Hill). 2.1. Agonists, Neutral
Antagonists, and Inverse Agonists. 2.2. LDTRS/Protean Agonism. 2.3.
Molecular Mechanisms of GPCR Ligand Binding. 2.4. Two GPCR Ligands Binding
at Once--Concept of Allosterism. 2.5. GPCR Dimerization. 2.6. Future
Perspectives. Acknowledgments. References. 3. The Emergence of Allosteric
Modulators for G Protein-Coupled Receptors (Karen J. Gregory, Celine
Valant, John Simms, Patrick M. Sexton, and Arthur Christopoulos). 3.1.
Introduction. 3.2. Foundations of Allosteric Receptor Theory. 3.3. Models
for Understanding the Effects of Allosteric Modulators. 3.4. Types of
Allosteric Modulators and Their Properties. 3.5. Detection and
Quantification of Allosteric Interactions. 3.6. Some Examples of GPCR
Allosteric Modulators. 3.7. Concluding Remarks. References. 4.
Receptor-Mediated G Protein Activation: How, How Many, and Where? (Ingrid
Gsandtner, Christian W. Gruber, and Michael Freissmuth). 4.1. The
Mechanical Problem--Three Different Solutions. 4.2. Receptor
Monomers-Dimers-Oligomers: One Size Fits All? 4.3. Corrals, Fences,
Rafts--Are There Privileged Places for GPCR Activation? Acknowledgments.
References. 5. Molecular Pharmacology of Frizzleds--with Implications for
Possible Therapy (Gunnar Schulte). 5.1. Introduction. 5.2. Frizzleds as WNT
Receptors. 5.3. Frizzled Signaling 120. 5.4. Frizzleds--Physiology and
Possible Therapy. Acknowledgments. References. 6. Secretin Receptor
Dimerization: A Possible Functionally Important Paradigm for Family B G
Protein-Coupled Receptors (Kaleeckal G. Harikumar, Maoqing Dong, and
Laurence J. Miller). 6.1. Methodological Approaches to GPCR
Oligomerization. 6.2. Structural Themes for GPCR Oligomerization. 6.3.
Functional Effects of GPCR Oligomerization. 6.4. Secretin Receptor
Oligomerization. References. 7. Past and Future Strategies for GPCR
Deorphanization (Angélique Levoye, Nathalie Clement, Elodie Tenconi and
Ralf Jockers). 7.1. Introduction. 7.2. Current Strategies to Identify the
Ligand and Function of Orphan 7TM Proteins. 7.3. Functional Assays for
Deorphanization. 7.4. Future Directions and New Concepts. 7.5.
Controversial Issues. Acknowledgments. References. 8. High-Throughput GPCR
Screening Technologies and the Emerging Importance of the Cell Phenotype
(Terry Reisine and Richard M. Eglen). 8.1. Introduction. 8.2. How Are GPCR
Drugs Discovered? 8.3. GPCR Dependence on G Proteins. 8.4. Technologies for
GPCR Compound Screening and Drug Discovery. 8.5. Importance of Target Cells
in GPCR HTS Assays. 8.6. Summary. References. 9. Are "Traditional"
Biochemical Techniques Out of Fashion in the New Era of GPCR Pharmacology?
(Maria Teresa Dell'anno and Maria Rosa Mazzoni). 9.1. Overview. 9.2.
Receptor Binding Assays. 9.3. Methods for Measurement of cAMP. 9.4.
Conclusions. References. 10. Fluorescence and Resonance Energy Transfer
Shine New Light on GPCR Function (Carsten Hoffmann and Moritz Bünemann).
10.1. Overview. 10.2. Introduction. 10.3. Labeling GPCRs with Fluorescent
Tags. 10.4. Detection of Fluorescence and Bioluminescence. 10.5.
Fluorescence-Based Assays to Study Receptor Localization, Trafficking and
Receptor Function. 10.6. Resonance Energy Transfer, a Tool to Get New
Insights into GPCR Function. 10.7. Analysis of Steady-State Protein-Protein
Interaction by Means of RET. 10.8. Kinetic Analysis of Protein-Protein
Interactions by Means of FRET. 10.9. Detection of Receptor Function by
Fluorescence Resonance Energy. References. 11. Integration of Label-Free
Detection Methods in GPCR Drug Discovery (Oliver Nayler, Magdalena
Birker-Robaczewska, and John Gatfield). 11.1. Overview. 11.2. Introduction.
11.3. Label-Free Technologies--Past and Present. 11.4. Discussion.
Acknowledgments. References. 12. Screening for Allosteric Modulators of G
Protein-Coupled Receptors (Christopher Langmead). 12.1. Introduction. 12.2.
The Allosteric Ternary Complex Model, Radioligand Binding, and Affinity.
12.3. Beyond Affinity--Functional Assays, Efficacy, and Allosteric Agonism.
12.4. Allosteric Modulator Titration Curves. 12.5. The Impact of Functional
Assay Format on Allosteric Modulator Screening. 12.6. Taking Advantage of
Structural Understanding of Allosteric Binding Sites. 12.7. Summary and
Future Directions. References. 13. Ultra-High-Throughput Screening Assays
for GPCRs (Priya Kunapuli). 13.1. Introduction. 13.2. Assay Types for GPCRs
in uHTS. 13.3. Summary. Acknowledgments. References. 14. New Techniques to
Express and Crystallize G Protein-Coupled Receptors (James C. Errey and
Fiona H. Marshall). 14.1. Introduction. 14.2. Key Problems Limiting
Production of 3D GPCR Structures. 14.3. History of GPCR Structures. 14.4.
The Search for Other GPCR Structures. 14.5. Protein Purification and
Solubilization. 14.6. In Cubo Crystallization. 14.7. Engineering Receptor
Stability. 14.8. Structures of the â2AR. 14.9. The Adenosine A2a Receptor.
14.10. Conclusions and Future Developments. Acknowledgments. References.
15. Structure and Modeling of GPCRs: Implications for Drug Discovery
(Kimberly A. Reynolds, Vsevolod Katritch, and Ruben Abagyan). 15.1.
Introduction. 15.2. High-Resolution GPCR Modeling. 15.3. Constructing and
Evaluating Homology Models of Other Receptor Types. 15.4. Modeling GPCR
Functional Features--Analysis of Activation and Signaling. 15.5. Beyond
Class A: Modeling of Other GPCR Families. 15.6. Summary and Conclusions.
Acknowledgments. References. 16. X-Ray Structure Developments for GPCR Drug
Targets (Michael Sabio and Sidney W. Topiol). 16.1. Overview. 16.2.
Introduction. 16.3. Class A GPCRs. 16.4. Class C GPCRs. 16.5. Conclusions.
References. 17. Pharmacological Chaperones: Potential for the Treatment of
Hereditary Diseases Caused by Mutations in G Protein-Coupled Receptors
(Kenneth J. Valenzano, Elfrida R. Benjamin,Patricia René, and Michel
Bouvier). 17.1. Overview. 17.2. Introduction. 17.3. NDI and the V2R. 17.4.
RP and the Rhodopsin Receptor. 17.5. IHH and the Gonadotropin-Releasing
Hormone Receptor. 17.6. Other Human Diseases Caused by Inactivating
Mutations in GPCRs. 17.7. Considerations for the Therapeutic Use of
Pharmacological Chaperones. 17.8. Concluding Remarks. Acknowledgments.
References. Index.
to Microprocessors (Terry Kenakin). 1.1. Introduction. 1.2. The Receptor as
an On-Off Switch. 1.3. Historical Background and Classical Receptor Theory.
1.4. The Operational Model of Drug Action. 1.5. Receptor Antagonism. 1.6.
Specific Models of GPCRs (7TM Receptors). 1.7. The Receptor as
Microprocessor: Ternary Complex Models. 1.8. Receptors as Basic Drug
Recognition Units. 1.9. Receptor Structure. 1.10. Future Considerations.
References. 2. The Evolving Pharmacology of GPCRs 27 (Lauren T. May,
Nicholas D. Holliday, and Stephen J. Hill). 2.1. Agonists, Neutral
Antagonists, and Inverse Agonists. 2.2. LDTRS/Protean Agonism. 2.3.
Molecular Mechanisms of GPCR Ligand Binding. 2.4. Two GPCR Ligands Binding
at Once--Concept of Allosterism. 2.5. GPCR Dimerization. 2.6. Future
Perspectives. Acknowledgments. References. 3. The Emergence of Allosteric
Modulators for G Protein-Coupled Receptors (Karen J. Gregory, Celine
Valant, John Simms, Patrick M. Sexton, and Arthur Christopoulos). 3.1.
Introduction. 3.2. Foundations of Allosteric Receptor Theory. 3.3. Models
for Understanding the Effects of Allosteric Modulators. 3.4. Types of
Allosteric Modulators and Their Properties. 3.5. Detection and
Quantification of Allosteric Interactions. 3.6. Some Examples of GPCR
Allosteric Modulators. 3.7. Concluding Remarks. References. 4.
Receptor-Mediated G Protein Activation: How, How Many, and Where? (Ingrid
Gsandtner, Christian W. Gruber, and Michael Freissmuth). 4.1. The
Mechanical Problem--Three Different Solutions. 4.2. Receptor
Monomers-Dimers-Oligomers: One Size Fits All? 4.3. Corrals, Fences,
Rafts--Are There Privileged Places for GPCR Activation? Acknowledgments.
References. 5. Molecular Pharmacology of Frizzleds--with Implications for
Possible Therapy (Gunnar Schulte). 5.1. Introduction. 5.2. Frizzleds as WNT
Receptors. 5.3. Frizzled Signaling 120. 5.4. Frizzleds--Physiology and
Possible Therapy. Acknowledgments. References. 6. Secretin Receptor
Dimerization: A Possible Functionally Important Paradigm for Family B G
Protein-Coupled Receptors (Kaleeckal G. Harikumar, Maoqing Dong, and
Laurence J. Miller). 6.1. Methodological Approaches to GPCR
Oligomerization. 6.2. Structural Themes for GPCR Oligomerization. 6.3.
Functional Effects of GPCR Oligomerization. 6.4. Secretin Receptor
Oligomerization. References. 7. Past and Future Strategies for GPCR
Deorphanization (Angélique Levoye, Nathalie Clement, Elodie Tenconi and
Ralf Jockers). 7.1. Introduction. 7.2. Current Strategies to Identify the
Ligand and Function of Orphan 7TM Proteins. 7.3. Functional Assays for
Deorphanization. 7.4. Future Directions and New Concepts. 7.5.
Controversial Issues. Acknowledgments. References. 8. High-Throughput GPCR
Screening Technologies and the Emerging Importance of the Cell Phenotype
(Terry Reisine and Richard M. Eglen). 8.1. Introduction. 8.2. How Are GPCR
Drugs Discovered? 8.3. GPCR Dependence on G Proteins. 8.4. Technologies for
GPCR Compound Screening and Drug Discovery. 8.5. Importance of Target Cells
in GPCR HTS Assays. 8.6. Summary. References. 9. Are "Traditional"
Biochemical Techniques Out of Fashion in the New Era of GPCR Pharmacology?
(Maria Teresa Dell'anno and Maria Rosa Mazzoni). 9.1. Overview. 9.2.
Receptor Binding Assays. 9.3. Methods for Measurement of cAMP. 9.4.
Conclusions. References. 10. Fluorescence and Resonance Energy Transfer
Shine New Light on GPCR Function (Carsten Hoffmann and Moritz Bünemann).
10.1. Overview. 10.2. Introduction. 10.3. Labeling GPCRs with Fluorescent
Tags. 10.4. Detection of Fluorescence and Bioluminescence. 10.5.
Fluorescence-Based Assays to Study Receptor Localization, Trafficking and
Receptor Function. 10.6. Resonance Energy Transfer, a Tool to Get New
Insights into GPCR Function. 10.7. Analysis of Steady-State Protein-Protein
Interaction by Means of RET. 10.8. Kinetic Analysis of Protein-Protein
Interactions by Means of FRET. 10.9. Detection of Receptor Function by
Fluorescence Resonance Energy. References. 11. Integration of Label-Free
Detection Methods in GPCR Drug Discovery (Oliver Nayler, Magdalena
Birker-Robaczewska, and John Gatfield). 11.1. Overview. 11.2. Introduction.
11.3. Label-Free Technologies--Past and Present. 11.4. Discussion.
Acknowledgments. References. 12. Screening for Allosteric Modulators of G
Protein-Coupled Receptors (Christopher Langmead). 12.1. Introduction. 12.2.
The Allosteric Ternary Complex Model, Radioligand Binding, and Affinity.
12.3. Beyond Affinity--Functional Assays, Efficacy, and Allosteric Agonism.
12.4. Allosteric Modulator Titration Curves. 12.5. The Impact of Functional
Assay Format on Allosteric Modulator Screening. 12.6. Taking Advantage of
Structural Understanding of Allosteric Binding Sites. 12.7. Summary and
Future Directions. References. 13. Ultra-High-Throughput Screening Assays
for GPCRs (Priya Kunapuli). 13.1. Introduction. 13.2. Assay Types for GPCRs
in uHTS. 13.3. Summary. Acknowledgments. References. 14. New Techniques to
Express and Crystallize G Protein-Coupled Receptors (James C. Errey and
Fiona H. Marshall). 14.1. Introduction. 14.2. Key Problems Limiting
Production of 3D GPCR Structures. 14.3. History of GPCR Structures. 14.4.
The Search for Other GPCR Structures. 14.5. Protein Purification and
Solubilization. 14.6. In Cubo Crystallization. 14.7. Engineering Receptor
Stability. 14.8. Structures of the â2AR. 14.9. The Adenosine A2a Receptor.
14.10. Conclusions and Future Developments. Acknowledgments. References.
15. Structure and Modeling of GPCRs: Implications for Drug Discovery
(Kimberly A. Reynolds, Vsevolod Katritch, and Ruben Abagyan). 15.1.
Introduction. 15.2. High-Resolution GPCR Modeling. 15.3. Constructing and
Evaluating Homology Models of Other Receptor Types. 15.4. Modeling GPCR
Functional Features--Analysis of Activation and Signaling. 15.5. Beyond
Class A: Modeling of Other GPCR Families. 15.6. Summary and Conclusions.
Acknowledgments. References. 16. X-Ray Structure Developments for GPCR Drug
Targets (Michael Sabio and Sidney W. Topiol). 16.1. Overview. 16.2.
Introduction. 16.3. Class A GPCRs. 16.4. Class C GPCRs. 16.5. Conclusions.
References. 17. Pharmacological Chaperones: Potential for the Treatment of
Hereditary Diseases Caused by Mutations in G Protein-Coupled Receptors
(Kenneth J. Valenzano, Elfrida R. Benjamin,Patricia René, and Michel
Bouvier). 17.1. Overview. 17.2. Introduction. 17.3. NDI and the V2R. 17.4.
RP and the Rhodopsin Receptor. 17.5. IHH and the Gonadotropin-Releasing
Hormone Receptor. 17.6. Other Human Diseases Caused by Inactivating
Mutations in GPCRs. 17.7. Considerations for the Therapeutic Use of
Pharmacological Chaperones. 17.8. Concluding Remarks. Acknowledgments.
References. Index.