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

Preface
Contents
Integrated Structural Studies for Elucidating Carotenoid-Protein Interactions
	1 Carotenoids and Carotenoproteins
	2 Hybrid Structural Methods in the Study of the OCP
	3 Hybrid Structural Methods in the Study of the HCPs and CCP
	4 Conclusions and Prospects
	References
The Non-continuum Nature of Eukaryotic Transcriptional Regulation
	1 Introduction
	2 Chapter 1. DNA Sequence and Protein-Protein Partnerships Mutually Direct Transcription Factor Interactions
	3 Chapter 2. Low-Affinity Transcription Regulation: New Perspectives to Combinatorial Control
	4 Chapter 3. Rethinking Combinatorial Control: Concept of Non-continuum Response
	5 Chapter 4. Dynamic Mechanisms in Non-continuum Responses
		5.1 Section 4.1. Importance of Conformational Dynamics in Combinatorial Control
		5.2 Chapter 4.2. Molecular Hydration in Non-continuum Tuning
		5.3 Chapter 4.3. Experimental and Computational Approaches to Molecular Dynamics and Hydration
	6 Chapter 5. Evolutionary Origins of Non-continuum Tuning
		6.1 Chapter 5.1. CRP-Like Motif
		6.2 Chapter 5.2. POU Transcription Factors
	7 Concluding Remarks
	References
Photoreceptor Phosphodiesterase (PDE6): Structure, Regulatory Mechanisms, and Implications for Treatment of Retinal Diseases
	1 Introduction: Overview of Role of PDE6 in Visual Transduction
	2 Cyclic Nucleotide Phosphodiesterase Superfamily
		2.1 Catalytic Domain of PDE6
		2.2 Regulatory GAF Domains of PDE6
			2.2.1 Five PDE Families Contain Regulatory GAF Domains
			2.2.2 PDE6 GAF Domains
	3 The Pγ Subunit Is a Multi-functional Regulator of PDE6 Activity
		3.1 Pγ Is an Intrinsically Disordered Protein
		3.2 Functional Domains of the Pγ Subunit
			3.2.1 N-Terminal Region of Pγ (Amino Acids 1-21)
			3.2.2 Polycationic Region of Pγ (Amino Acids 22-45)
			3.2.3 Glycine-Rich Region of Pγ (Amino Acids 46-62)
			3.2.4 C-Terminal Region of Pγ (Amino Acids 63-87)
	4 Structural Biology of the PDE6 Holoenzyme
		4.1 Overall Domain Organization of the PDE6 Holoenzyme
		4.2 Three-Dimensional Structure of the Nonactivated PDE6 Holoenzyme
		4.3 Allosteric Communication Pathway of PDE6 Holoenzyme
			4.3.1 Biochemical Evidence for Allosteric Communication in PDE6
			4.3.2 Structural Studies Evaluating Conformational Changes Upon cGMP or Pγ Binding
	5 Mechanism of PDE6 Catalytic Activation by Transducin During Visual Excitation
		5.1 Biochemical Insights into the Mechanism of Gα* Activation of PDE6
			5.1.1 Activation by Transducin Is Enhanced When Gα* and PDE6 Are Membrane-Associated
			5.1.2 Gα*-Activated PDE6 Can Attain the Same Maximal Extent of Activation as the Pαβ Catalytic Dimer Lacking Pγ
			5.1.3 Two Gα* Molecules Per PDE6 Holoenzyme Are Required for Maximal Activation of PDE6 Catalysis
			5.1.4 The Sequential Mechanism of Transducin Activation of PDE6 Has Not Been Elucidated
			5.1.5 Gα* Activation of PDE6 Alters cGMP Binding to the GAFa Domains
		5.2 Structural Studies of the Gα*-PDE6 Complex
			5.2.1 Structure of the Gα*-PDE6 Activation Complex Obtained Using XL-MS
			5.2.2 Cryo-EM Structure of the Gα*-PDE6 Complex
			5.2.3 The Sequential Mechanism of Transducin Activation of PDE6 Remains Unresolved
	6 Molecular Etiology of Retinal Diseases Associated with Inherited Defects in PDE6 Genes
		6.1 Retinal Diseases Associated with Mutations in the Catalytic Subunits of PDE6
		6.2 Retinal Diseases Associated with Mutations in Pγ Subunit
	7 Pharmacotherapeutic Approaches to Modulating PDE6 Activity
		7.1 Many Compounds Designed to Inhibit PDE5 Also Inhibit PDE6
		7.2 Future Prospects for Drugs and Interfering Peptides Targeting Allosteric Sites or Protein-Protein Interfaces in PDE6
	8 Conclusion
	References
Rhodopsin as a Molecular Target to Mitigate Retinitis Pigmentosa
	1 Introduction
	2 Structure of Rhodopsin
	3 Function of Rhodopsin
	4 Structural Bases of Rhodopsin Misfolding
	5 Pharmacological Approaches to Develop Treatments for RP
		5.1 Modulators of Rhodopsin Expression
		5.2 Modulators of Misfolded Rhodopsin
			5.2.1 Kosmotropes
			5.2.2 Pharmacochaperones of Rhodopsin
				Retinoid-Based Pharmacological Chaperones
					13-cis-5,8-ERA
				Non-Retinoid Small Molecules Modulators
					NSC45012
					Retinobenzaldehydes
					YC-001
					RS1
					Flavonoids
	6 Concluding Remarks and Future Directions
	References
Elasticity-Associated Functionality and Inhibition of the HIV Protease
	1 Introduction
	2 The Tertiary Structure of the HIV Protease
	3 The Emergence of Resistance in HIV Protease
	4 Primary Resistance Mutations: Changes in the Active Site Geometry
	5 Non-active Site Mutations Associated with Drug Resistance
	6 The Role of Gag Mutations in Resistance
	7 Flexibility-Assisted Functionality of the PR
	8 Allosteric Inhibition of the PR
	9 Conclusions
	References
Single-Run Catalysis and Kinetic Control of Human Telomerase Holoenzyme
	1 Basics of Human Telomerase Holoenzyme and Importance of Its Kinetic Control
	2 Human Telomeres Switch Between Inaccessible and Accessible States
	3 Single-Run Catalysis by Human Telomerase Holoenzymes
	4 Thermodynamic Considerations of the Telomerase Catalysis
	5 Fast and Slow Active Sites in Telomerase Holoenzymes
	6 iTAFs as a Positive Regulator of the Telomerase Active Sites
	7 A Probabilistic View of Telomere Extension and Two Pools of Telomerase Holoenzymes
	8 Technical Limitations in Kinetic Analysis of Telomerase and Possible Solutions
	9 Conclusions and Future Directions
	References
Index