Viral Membrane Proteins: Structure, Function, and Drug Design (eBook)

Contents 6
List of Contributors 14
Preface 17
Part I Membrane Proteins from Plant Viruses 19
Membrane Proteins in Plant Viruses 20
1. Introduction 20
2. Survey of Transmembrane Proteins in Plant Viruses 20
3. Cell-to-Cell Movement Proteins 21
4. Replication Proteins 26
5. Proteins Involved in Transmission by Vectors 27
6. Other Membrane Proteins 30
7. Conclusions 31
Acknowledgments 31
References 31
Structure and Function of a Viral Encoded K+ Channel 37
1. Introduction 37
2. K+ Channels are Highly Conserved Proteins with Important Physiological Functions 38
3. Structural Aspects of Viral K+ Channel Proteins as Compared to those from Other Sources 38
4. The Short N-Terminus is Important for Kcv Function 40
5. Functional Properties of Kcv Conductance in Heterologous Expression Systems 41
6. Kcv is a K+ Selective Channel 41
7. Kcv has Some Voltage Dependency 41
8. Kcv has Distinct Sensitivity to K+ Channel Blockers 42
9. Ion Channel Function in Viral Replication 43
10. Kcv is Important for Viral Replication 44
11. Evolutionary Aspects of the kcv Gene 45
Acknowledgments 46
Part II Fusion Proteins 49
HIV gp41: A Viral Membrane Fusion Machine 50
1. Introduction 50
2. HIV Envelope Native Conformation 51
3. Receptor-Induced Conformational Changes 52
4. The Actual Membrane Fusion Step 54
5. HIV Entry Inhibitors 56
6. Final Remarks 58
Acknowledgment 58
References 59
Diversity of Coronavirus Spikes: Relationship to Pathogen Entry and Dissemination 63
1. Introduction 63
2. S Functions During Coronavirus Entry 65
3. S Functions During Dissemination of Coronavirus Infections 68
4. S Polymorphisms Affect Coronavirus Pathogenesis 69
5. Applications to the SARS Coronavirus 72
6. Relevance to Antiviral Drug Developments 73
Aspects of the Fusogenic Activity of Influenza Hemagglutinin Peptides by Molecular Dynamics Simulations 78
1. Introduction 78
2. Methods 80
3. Results 80
4. Conclusions 86
Acknowledgments 86
Part III Viral Ion Channels/ viroporins 89
Viral Proteins that Enhance Membrane Permeability 90
1. Introduction 90
2. Measuring Alterations in Membrane Permeability 91
3. Viral Proteins that Modify Permeability 94
4. Membrane Permeabilization and Drug Design 97
Acknowledgments 99
FTIR Studies of Viral Ion Channels 102
1. Introduction 102
2. SSID FTIR 103
3. Examples 107
4. Future Directions 109
Acknowledgment 110
References 111
The M2 Proteins of Influenza A and B Viruses are Single- Pass Proton Channels 112
1. Introduction 112
2. Intrinsic Activity of the A/M2 Protein of Influenza Virus 113
3. Mechanisms for Ion Selectivity and Activation of the A/ M2 Ion Channel 116
4. The BM2 Ion Channel of Influenza B Virus 118
5. Conclusion 120
Acknowledgments 120
Influenza A Virus M2 Protein: Proton Selectivity of the Ion Channel, Cytotoxicity, and a Hypothesis on Peripheral Raft Association and Virus Budding 123
1. Determination of Ion Selectivity and Unitary Conductance 124
2. Cytotoxicity of Heterologous M2 Expression 129
3. The M2 Protein Associates with Cholesterol 129
4. M2 as a Peripheral Raft Protein and a Model of its Role in Virus Budding 132
Acknowledgment 136
Computer Simulations of Proton Transport Through the M2 Channel of the Influenza A Virus 141
1. Introduction 141
2. Overview of Experimental Results for the M2 Channel 142
3. Molecular Dynamics Simulations of Proton Transport in the M2 Channel 144
4. Possible Closed and Open Conformations 146
5. A Revised Gating Mechanism and Future Work 152
Acknowledgments 152
References 152
Structure and Function of Vpu from HIV-1 156
1. Introduction 156
2. Structure Determination of Vpu 157
3. Correlation of Structure and Function of Vpu 162
4. Summary 167
Acknowledgments 168
Structure, Phosphorylation, and Biological Function of the HIV- 1 Specific Virus Protein U ( Vpu) 173
1. Introduction 174
2. Structure and Biochemistry of Vpu 175
3. Biochemical Analysis of Vpu Phosphorylation 178
Solid-State NMR Investigations of Vpu Structural Domains in Oriented Phospholipid Bilayers: Interactions and Alignment 184
1. Introduction 184
2. Peptide Synthesis 186
3. Results and Discussion 188
Acknowledgments 192
Defining Drug Interactions with the Viral Membrane Protein Vpu from HIV- 1 194
1. Introduction 194
2. The Methods 196
3. Analysis of Drug–Protein Interactions of Vpu with a Potential Blocker 197
4. How Realistic is the Protein Model? 203
5. The Putative Binding Site 204
6. Water in the Pore 205
7. MD Simulations for Drug Screening? 206
8. Other Viral Ion Channels and Blockers 206
9. Speculation of Binding Sites in the Cytoplasmic Site 207
10. Conclusions 207
Acknowledgments 207
References 207
Virus Ion Channels Formed by Vpu of HIV- 1, the 6K Protein of Alphaviruses and NB of Influenza B Virus 213
1. Virus Ion Channels 213
2. Vpu of HIV-1 215
3. Alphavirus 6K Proteins 222
4. NB of Influenza B Virus 228
The Alphavirus 6K Protein 238
1. Introduction 238
2. Methods to Assess Whether 6K is a Membrane- Active Protein 239
3. Synthesis of 6K During Virus Infection 243
4. Cell Membrane Permeabilization by 6K 243
5. Function of 6K During the Alphavirus Life Cycle 245
6. A Model of 6K Function in Virion Budding 246
Acknowledgments 247
Part IV Membrane- Spanning/Membrane Associated 250
The Structure, Function, and Inhibition of Influenza Virus Neuraminidase 251
1. Introduction 251
2. Structure of Influenza Virus Neuraminidase 253
3. Function of Influenza Virus Neuraminidase 259
4. Inhibition of Influenza Virus Neuraminidase 263
5. Conclusions 269
Acknowledgments 269
Interaction of HIV-1 Nef with Human CD4 and Lck 272
1. Introduction 272
2. Interaction of Nef with Human CD4 273
3. Interaction of Nef with Human Lck 281
Index 290