Protein Reviews: Volume 22 (Advances in Experimental Medicine and Biology, Volume 1371)

The __Protein Reviews__ series serves as a publication vehicle for reviews that focus on crucial contemporary and vital aspects of protein structure, function, evolution and genetics. Volumes are published online first, prior to publication in a printed book. Chapters are selected according to their importance to the understanding of biological systems, relevance to the unravelling of issues associated with health and disease, or impact on scientific or technological advances and developments. Volume 22 presents six review chapters authored by experts in related fields. The first chapter covers carotenoid-protein interactions. Chapter two addresses the non-continuum of eukaryotic transcriptional regulation. The third chapter reviews the structure of the regulatory and catalytic domains of the photoreceptor phosphodiesterase (PDE6) holoenzyme. Chapter four reviews the current knowledge on small molecule compounds that have been evaluated as rhodopsin modulators to be considered as leads for the development of novel therapies for retinitis pigmentosa. Chapter five deals with Plasticity-associated functionality and inhibition of the HIV protease. Finally, chapter six covers single-run catalysis and kinetic control of human telomerase holoenzyme. This volume is intended for research scientists, clinicians, physicians and graduate students in the fields of biochemistry, cell biology, molecular biology, immunology and genetics. \ Preface 6 Contents 8 Integrated Structural Studies for Elucidating Carotenoid-Protein Interactions 9 1 Carotenoids and Carotenoproteins 9 2 Hybrid Structural Methods in the Study of the OCP 10 3 Hybrid Structural Methods in the Study of the HCPs and CCP 15 4 Conclusions and Prospects 16 References 17 The Non-continuum Nature of Eukaryotic Transcriptional Regulation 19 1 Introduction 19 2 Chapter 1. DNA Sequence and Protein-Protein Partnerships Mutually Direct Transcription Factor Interactions 21 3 Chapter 2. Low-Affinity Transcription Regulation: New Perspectives to Combinatorial Control 24 4 Chapter 3. Rethinking Combinatorial Control: Concept of Non-continuum Response 27 5 Chapter 4. Dynamic Mechanisms in Non-continuum Responses 28 5.1 Section 4.1. Importance of Conformational Dynamics in Combinatorial Control 28 5.2 Chapter 4.2. Molecular Hydration in Non-continuum Tuning 31 5.3 Chapter 4.3. Experimental and Computational Approaches to Molecular Dynamics and Hydration 32 6 Chapter 5. Evolutionary Origins of Non-continuum Tuning 32 6.1 Chapter 5.1. CRP-Like Motif 33 6.2 Chapter 5.2. POU Transcription Factors 33 7 Concluding Remarks 33 References 35 Photoreceptor Phosphodiesterase (PDE6): Structure, Regulatory Mechanisms, and Implications for Treatment of Retinal Diseases 41 1 Introduction: Overview of Role of PDE6 in Visual Transduction 42 2 Cyclic Nucleotide Phosphodiesterase Superfamily 42 2.1 Catalytic Domain of PDE6 43 2.2 Regulatory GAF Domains of PDE6 45 2.2.1 Five PDE Families Contain Regulatory GAF Domains 45 2.2.2 PDE6 GAF Domains 45 3 The Pγ Subunit Is a Multi-functional Regulator of PDE6 Activity 46 3.1 Pγ Is an Intrinsically Disordered Protein 46 3.2 Functional Domains of the Pγ Subunit 47 3.2.1 N-Terminal Region of Pγ (Amino Acids 1-21) 47 3.2.2 Polycationic Region of Pγ (Amino Acids 22-45) 47 3.2.3 Glycine-Rich Region of Pγ (Amino Acids 46-62) 48 3.2.4 C-Terminal Region of Pγ (Amino Acids 63-87) 48 4 Structural Biology of the PDE6 Holoenzyme 49 4.1 Overall Domain Organization of the PDE6 Holoenzyme 50 4.2 Three-Dimensional Structure of the Nonactivated PDE6 Holoenzyme 50 4.3 Allosteric Communication Pathway of PDE6 Holoenzyme 51 4.3.1 Biochemical Evidence for Allosteric Communication in PDE6 51 4.3.2 Structural Studies Evaluating Conformational Changes Upon cGMP or Pγ Binding 52 5 Mechanism of PDE6 Catalytic Activation by Transducin During Visual Excitation 54 5.1 Biochemical Insights into the Mechanism of Gα* Activation of PDE6 54 5.1.1 Activation by Transducin Is Enhanced When Gα* and PDE6 Are Membrane-Associated 54 5.1.2 Gα*-Activated PDE6 Can Attain the Same Maximal Extent of Activation as the Pαβ Catalytic Dimer Lacking Pγ 54 5.1.3 Two Gα* Molecules Per PDE6 Holoenzyme Are Required for Maximal Activation of PDE6 Catalysis 54 5.1.4 The Sequential Mechanism of Transducin Activation of PDE6 Has Not Been Elucidated 54 5.1.5 Gα* Activation of PDE6 Alters cGMP Binding to the GAFa Domains 55 5.2 Structural Studies of the Gα*-PDE6 Complex 55 5.2.1 Structure of the Gα*-PDE6 Activation Complex Obtained Using XL-MS 55 5.2.2 Cryo-EM Structure of the Gα*-PDE6 Complex 57 5.2.3 The Sequential Mechanism of Transducin Activation of PDE6 Remains Unresolved 57 6 Molecular Etiology of Retinal Diseases Associated with Inherited Defects in PDE6 Genes 58 6.1 Retinal Diseases Associated with Mutations in the Catalytic Subunits of PDE6 59 6.2 Retinal Diseases Associated with Mutations in Pγ Subunit 59 7 Pharmacotherapeutic Approaches to Modulating PDE6 Activity 59 7.1 Many Compounds Designed to Inhibit PDE5 Also Inhibit PDE6 60 7.2 Future Prospects for Drugs and Interfering Peptides Targeting Allosteric Sites or Protein-Protein Interfaces in PDE6 61 8 Conclusion 61 References 62 Rhodopsin as a Molecular Target to Mitigate Retinitis Pigmentosa 68 1 Introduction 68 2 Structure of Rhodopsin 69 3 Function of Rhodopsin 70 4 Structural Bases of Rhodopsin Misfolding 72 5 Pharmacological Approaches to Develop Treatments for RP 74 5.1 Modulators of Rhodopsin Expression 74 5.2 Modulators of Misfolded Rhodopsin 75 5.2.1 Kosmotropes 75 5.2.2 Pharmacochaperones of Rhodopsin 75 Retinoid-Based Pharmacological Chaperones 75 13-cis-5,8-ERA 77 Non-Retinoid Small Molecules Modulators 77 NSC45012 77 Retinobenzaldehydes 78 YC-001 78 RS1 79 Flavonoids 79 6 Concluding Remarks and Future Directions 80 References 80 Elasticity-Associated Functionality and Inhibition of the HIV Protease 85 1 Introduction 85 2 The Tertiary Structure of the HIV Protease 86 3 The Emergence of Resistance in HIV Protease 88 4 Primary Resistance Mutations: Changes in the Active Site Geometry 91 5 Non-active Site Mutations Associated with Drug Resistance 92 6 The Role of Gag Mutations in Resistance 98 7 Flexibility-Assisted Functionality of the PR 99 8 Allosteric Inhibition of the PR 103 9 Conclusions 109 References 110 Single-Run Catalysis and Kinetic Control of Human Telomerase Holoenzyme 115 1 Basics of Human Telomerase Holoenzyme and Importance of Its Kinetic Control 115 2 Human Telomeres Switch Between Inaccessible and Accessible States 117 3 Single-Run Catalysis by Human Telomerase Holoenzymes 120 4 Thermodynamic Considerations of the Telomerase Catalysis 122 5 Fast and Slow Active Sites in Telomerase Holoenzymes 123 6 iTAFs as a Positive Regulator of the Telomerase Active Sites 127 7 A Probabilistic View of Telomere Extension and Two Pools of Telomerase Holoenzymes 127 8 Technical Limitations in Kinetic Analysis of Telomerase and Possible Solutions 128 9 Conclusions and Future Directions 130 References 131 Index 136 "The Protein Reviews series serves as a publication vehicle for reviews that focus on crucial contemporary and vital aspects of protein structure, function, evolution and genetics. Volumes are published online first, prior to publication in a printed book. Chapters are selected according to their importance to the understanding of biological systems, relevance to the unravelling of issues associated with health and disease, or impact on scientific or technological advances and developments. Volume 22 presents six review chapters authored by experts in related fields. The first chapter covers carotenoid-protein interactions. Chapter two addresses the non-continuum of eukaryotic transcriptional regulation. The third chapter reviews the structure of the regulatory and catalytic domains of the photoreceptor phosphodiesterase (PDE6) holoenzyme. Chapter four reviews the current knowledge on small molecule compounds that have been evaluated as rhodopsin modulators to be considered as leads for the development of novel therapies for retinitis pigmentosa. Chapter five deals with Plasticity-associated functionality and inhibition of the HIV protease. Finally, chapter six covers single-run catalysis and kinetic control of human telomerase holoenzyme. This volume is intended for research scientists, clinicians, physicians and graduate students in the fields of biochemistry, cell biology, molecular biology, immunology and genetics."--Page 4 de la couverture