Synopses & Reviews
Protein Reviews, a new book series from Springer, covers all aspects of protein investigations including protein chemistry, sequence, 3-D structure, biological activity, proteomics, methodology, and many more new and emerging topics. Volume 1: Viral Membrane Proteins: Structure, Function and Drug Design Edited by Wolfgang B. Fischer This volume, written by renowned leaders in the field, summarizes the current structural and functional knowledge of membrane proteins encoded by viruses while addressing questions about the proteins as potential drug targets. Early praise for this volume: "We all know that you can't treat viral disease with drugs.....That was what all physicians and scientists were taught for decades with conviction but without enough experiments. Fortunately, we were taught wrong: rationally designed drugs are available that work well against influenza as Garman and Laver describe so well (with the help of Wen Yang Wu) in a fascinating chapter of this book. In fact, viral membrane proteins have a range of functions of great medical and biological importance, not so surprisingly if one understands that membrane proteins control a wide range of function because they are gatekeepers for cells. Membrane proteins control entry into cells and viruses. Viral Membrane Proteins" is a wonderful description of some of these proteins. The authors and editor are to be congratulated on producing much more than a collection of reviews and essays. This book can help teach everyone that it is possible to treat viral disease with drugs that bind to membrane proteins. Knowing that, we can hope that more resources will be focused on finding other such drugs to the remaining scourges of mankind, at least those we do not produce ourselves." - Robert S. Eisenberg, Rush University Medical Center, Chicago, IL <>
Synopsis
In Viral Membrane Proteins: Structure, Function, and Drug Design, Wolfgang Fischer summarizes the current structural and functional knowledge of membrane proteins encoded by viruses. In addition, contributors to the book address questions about proteins as potential drug targets. The range of information covered includes signal proteins, ion channels, and fusion proteins. This book has a place in the libraries of researchers and scientists in a wide array of fields, including protein chemistry, molecular biophysics, pharmaceutical science and research, bioanotechnology, molecular biology, and biochemistry.
Table of Contents
Part I. Membrane Proteins from Plant Viruses 1. Membrane Proteins in Plant Viruses Michael J. Adams and John F. Antoniw 1. Introduction 2. Survey of Transmembrane Proteins in Plant Viruses 2.1. The Database 2.2. Software 3. Cell-To-Cell Movement Proteins 3.1. The "30k" Superfamily 3.2. Triple Gene Block 3.3. Carmovirus-Like 3.4. Other Movement Proteins 3.5. General Comments 4. Replication Proteins 5. Proteins Involved in Transmission by Vectors 5.1. Insect Transmission 5.2. Fungus Transmission 6. Other Membrane Proteins 7. Conclusions Acknowledgments References 2. Structure and Function of a Viral Encoded K Channel Anna Moroni, James Van Etten, and Gerhard Thiel 1. Introduction 2. K Channels are Highly Conserved Proteins with Important Physiological Functions 3. Structural Aspects of Viral K Channel Proteins as Compared to those from Other Sources 4. The Short N-Terminus is Important for Kcv Function 5. Functional Properties of Kcv Conductance in Heterologous Expression Systems 6. Kcv is a K Selective Channel 7. Kcv has some Voltage Dependency 8. Kcv has Distinct Sensitivity to K Channel Blockers 9. Ion Channel Function in Viral Replication v Vimp-FM.qxd 17/07/2004 03:07 PM Page v 10. Kcv is Important for Viral Replication 11. Evolutionary Aspects of the Kcv Gene Acknowledgments References Part II. Fusion Proteins 3. HIV gp41: A Viral Membrane Fusion Machine Sergio G. Peisajovich and Yechiel Shai 1. Introduction 2. HIV Envelope Native Conformation 3. Receptor-Induced Conformational Changes 3.1. CD4 Interaction 3.2. Co-Receptor Interaction 4. The Actual Membrane Fusion Step 4.1. The Role of the N-Terminal Fusion Domain 4.2. The Role of the C-Terminal Fusion Domain 5. HIV Entry Inhibitors 5.1. CD4-Binding Inhibitors 5.2. Co-Receptor Binding Inhibitors 5.3. Improving the Activity of Inhibitors that Block Conformational Changes 6. Final Remarks Acknowledgment References 4. Diversity of Coronavirus Spikes: Relationship to Pathogen Entry and Dissemination Edward B. Thorp and Thomas M. Gallagher 1. Introduction 2. S Functions during Coronavirus Entry 3. S Functions during Dissemination of Coronavirus Infections 4. S Polymorphisms Affect Coronavirus Pathogenesis 5. Applications to the SARS Coronavirus 6. Relevance to Antiviral Drug Developments References 5. Aspects of the Fusogenic Activity of Influenza Hemagglutinin Peptides by Molecular Dynamics Simulations L. Vaccaro, K. Cross, S.A. Wharton, J.J. Skehel, and F. Fraternali 1. Introduction 2. Methods 3. Results 3.1. Comparison with Experimental Structures 3.2. Membrane Anchoring vi Contents Vimp-FM.qxd 17/07/2004 03:07 PM Page vi Contents vii 4. Conclusions Acknowledgment References Part III. Viral Ion Channels/Viroporins 6. Viral Proteins that Enhance Membrane Permeability María Eugenia González and Luis Carrasco 1. Introduction 2. Measuring Alterations in Membrane Permeability 2.1. The Hygromycin B Test 2.2. Entry of Macromolecules into Virus-Infected Cells 2.3. Other Assays to Test the Entry or Exit of Macromolecules from Virus-Infected Cells 2.3.1. Entry or Exit of Radioactive Molecules 2.3.2. Entry of ONPG and Dyes 2.3.3. Entry of Propidium Iodide 2.3.4. Release of Cellular Enzymes to Culture Medium 3. Viral Proteins that Modify Permeability 3.1. Viroporins 3.2. Viral Glycoproteins that Modify Membrane Permeability 3.2.1. Rotavirus Glycoprotein 3.2.2. The HIV-1 gp41 3.2.3. Other Viral Glycoproteins 4. Membrane Permeabilization and Drug Design 4.1. Antibiotics and Toxins that Selectively Enter Virus-Infected Cells 4.2. Viroporin Inhibitors 4.3. Antiviral Agents that Interfere with Viral Glycoproteins Acknowledgments References 7. FTIR Studies of Viral Ion Channels Itamar Kass and Isaiah T. Arkin 1. Introduction 1.1. Principles of Infrared Spectroscopy 1.1.1. Amide Group Vibrations 1.1.2. Secondary Structure 2. SSID FTIR 2.1. Dichroic Ratio 2.2. Sample Disorder 2.3. Orientational Parameters Derivation 2.4. Data Utilization 3. Examples 3.1. M2 H Channel from Influenza A Virus 3.2. vpu Channel from HIV 3.3. CM2 from Influenza C Virus Vimp-FM.qxd 17/07/2004 03:07 PM Page vii 4. Future Directions Acknowledgment References 8. The M2 Proteins of Influenza A and B Viruses are Single-Pass Proton Channels Yajun Tang, Padma Venkataraman, Jared Knopman, Robert A. Lamb, and Lawrence H. Pinto 1. Introduction 2. Intrinsic Activity of the A/M2 Protein of Influenza Virus 3. Mechanisms for Ion Selectivity and Activation of the A/M2 Ion Channel 4. The BM2 Ion Channel of Influenza B Virus 5. Conclusion Acknowledgments References 9. Influenza A Virus M2 Protein: Proton Selectivity of the Ion Channel, Cytotoxicity, and a Hypothesis on Peripheral Raft Association and Virus Budding Cornelia Schroeder and Tse-I Lin 1. Determination of Ion Selectivity and Unitary Conductance` 1.1. Background 1.2. Method 1.2.1. Expression, Isolation, and Quantification of the M2 Protein 1.2.2. Reconstitution of M2 into Liposomes 1.2.3. Proton Translocation Assay 1.3. Proton Selectivity 1.4. Average Single-Channel Parameters and Virion Acidification during Uncoating 2. Cytotoxicity of Heterologous M2 Expression 3. The M2 Protein Associates with Cholesterol 4. M2 as a Peripheral Raft Protein and a Model of its Role in Virus Budding 4.1. Interfacial Hydrophobicity and Potential Cholesterol and Raft-Binding Motifs of the M2 Post-TM Region 4.2. M2 as a Peripheral Raft Protein 4.3. M2 as a Factor in the Morphogenesis and Pinching-Off of Virus Particles Acknowledgment References 10. Computer Simulations of Proton Transport Through the M2 Channel of the Influenza A Virus Yujie Wu and Gregory A. Voth 1. Introduction 2. Overview of Experimental Studies for the M2 Channel 2.1. The Roles of the M2 Channel in the Viral Life Cycle 2.2. The Architecture of the M2 Channel 2.3. Ion Conductance Mechanisms 3. Molecular Dynamics Simulations of Proton Transport in the M2 Channel viii Contents Vimp-FM.qxd 17/07/2004 03:07 PM Page viii 3.1. Explicit Proton Transport Simulations and Properties of the Excess Proton in the M2 Channel 3.2. Implications for the Proton Conductance Mechanism 4. Possible Closed and Open Conformations 4.1. A Possible Conformation for the Closed M2 Channel 4.2. A Possible Conformation for the Open M2 Channel 4.3. Further MD Simulations with the Closed Structure 5. A Revised Gating Mechanism and Future Work Acknowledgments References 11. Structure and Function of Vpu from HIV-1 S.J. Opella, S. Park, S. Lee, D. Jones, A. Nevzorov, M. Mesleh, A. Mrse, F.M. Marassi, M. Oblatt-Montal, M. Montal, S. Bour, and K. Strebel 1. Introduction 2. Structure Determination of Vpu 3. Correlation of Structure and Function of Vpu 4. Vpu-Mediated Enhancement of Viral Particle Release 5. Vpu-Mediated Degradation of the Cd4 Receptor 6. Summary Acknowledgments References 12. Structure, Phosphorylation, and Biological Function of the HIV-1 Specific Virus Protein U (Vpu) Victor Wray and Ulrich Schubert 1. Introduction 2. Structure and Biochemistry of Vpu 3. Biochemical Analysis of Vpu Phosphorylation References 13. Solid-State NMR Investigations of Vpu Structural Domains in Oriented Phospholipid Bilayers: Interactions and Alignment Burkhard Bechinger and Peter Henklein 1. Introduction 2. Peptide Synthesis 3. Results and Discussion Acknowledgments References 14. Defining Drug Interactions with the Vpu Ion Channel from HIV-1 V. Lemaitre, C.G. Kim, D. Fischer, Y.H. Lam, A. Watts, and W.B. Fischer 1. Introduction 1.1. Short Viral Membrane Proteins 1.2. The Vpu Protein 2. The Methods Contents ix Vimp-FM.qxd 17/07/2004 03:07 PM Page ix 2.1. Docking Approach 2.2. Molecular Dynamics (MD) Simulations 3. Analysis of Drug-Protein Interactions of Vpu with a Potential Blocker 3.1. Using the Docking Approach 3.2. Applying MD Simulations 4. How Realistic is the Protein Model? 5. The Putative Binding Site 6. Water in the Pore 7. MD Simulations for Drug Screening? 8. Other Viral Ion Channels and Blockers 9. Speculation of Binding Sites in the Cytoplasmic Site 10. Conclusions Acknowledgments References 15. Virus Ion Channels Formed by Vpu of HIV-1, the 6K Protein of Alphaviruses and NB of Influenza B Virus Peter W. Gage, Gary Ewart, Julian Melton, and Anita Premkumar 1. Virus Ion Channels 2. Vpu of HIV-1 2.1. Roles of Vpu in HIV-1 Replication 2.2. Evidence that Vpu Forms an Ion Channel 2.2.1. Properties of the Vpu Channel 2.3. The Link Between Budding Enhancement by Vpu and its Ion Channel Activity 2.3.1. Mutants Lacking Ion Channel Activity and Virus Budding 2.3.2. Channel Blocking Drugs Inhibit Budding 2.3.3. HMA Inhibits HIV-1 Replication in Monocytes and Macrophages 3. Alphavirus 6K Proteins 3.1. Replication of Alphaviruses 3.2. The 6K Protein of Alphaviruses 3.3. The 6K Protein and Virus Budding 3.4. Ion Channels Formed by BFV and RRV 6K Protein 3.5. Antibody Inhibition of RRV 6K Channels 4. NB of Influenza B Virus 4.1. Structure of NB 4.2. Similarities Between M2 and NB 4.3. Channel Activity of the NB Protein 4.4. Currents at pH 6.0 4.5. Currents at pH 2.5 4.6. Effect of C-Terminal Antibody 4.7. Effect of Amantadine 4.8. Proton Permeability of NB Ion Channels References 16. The Alphavirus 6K Protein M.A. Sanz, V. Madan, J.L. Nieva, and L. Carrasco 1. Introduction 2. Methods to Assess Whether 6K is a Membrane-Active Protein x Contents Vimp-FM.qxd 17/07/2004 03:07 PM Page x Contents xi 2.1. Hydrophobicity Tests 2.2. Inducible Synthesis of 6K in E. Coli 2.3. Synthesis of 6K in Mammalian Cells 3. Synthesis of 6K During Virus Infection 4. Cell Membrane Permeabilization by 6K 5. Function of 6K During the Alphavirus Life Cycle 6. A Model of 6K Function in Virion Budding Acknowledgments References Part IV. Membrane-Associated/Membrane Spanning 17. The Structure, Function, and Inhibition of Influenza Virus Neuraminidase Elspeth Garman and Graeme Laver 1. Introduction 1.1. Structure of Influenza Virus 2. Structure of Influenza Virus Neuraminidase 2.1. Crystallization of Influenza Virus Neuraminidase 2.2. Structure of the Conserved Catalytic Site 2.3. Structures of Other Influenza Virus Neuraminidases 2.4. Hemagglutinin Activity of Neuraminidase 3. Function of Influenza Virus Neuraminidase 3.1. Antigenic Properties of Influenza Virus Neuraminidase 3.2. Antigenic Drift in Influenza Virus Neuraminidase 4. Inhibition of Influenza Virus Neuraminidase 4.1. Design and Synthesis of Novel Inhibitors of Influenza Virus Neuraminidase 4.1.1. Relenza 4.1.2. Tamiflu 4.1.3. Other Inhibitors of Influenza Virus Neuraminidase 4.2. Drug Resistance 5. Conclusions Acknowledgments References 18. Interaction of HIV-1 Nef with Human CD4 and Lck Dieter Willbold 1. Introduction 2. Interaction of Nef with Human CD4 2.1. The CD4 Receptor 2.2. CD4 and HIV 2.3. Three-Dimensional Structures of CD4 Cytoplasmic Domain and HIV-1 Nef 2.4. Nef Residues that are Important for CD4 Binding Map to the "Core Domain" 2.5. Amino Terminal Residues of Nef are also Important for CD4 Binding 2.6. Leucines 413 and 414 of CD4 are Essential for Nef Binding 2.7. High Affinity Between CD4(403-433) and Full-Length Nef can be Confirmed by NMR Spectroscopy Vimp-FM.qxd 17/07/2004 03:07 PM Page xi 2.8. The Presence of a Helix in Human CD4 Cytoplasmic Domain Promotes Binding to HIV-1 Nef Protein 2.9. Summary of the CD4-Nef Interaction 3. Interaction of Nef with Human Lck 3.1. Lymphocyte Specific Kinase Lck 3.2. X-Ray Structures of Nef-SH3 Complexes 3.3. NMR Spectroscopy is a Suitable Tool to Map Nef-Lck Interaction Sites 3.4. The Unique Domain of Lck is Not Involved in Nef Binding 3.5. Mapping of the Nef Interaction Site on Lck SH3 3.6. Summary of the Lck-Nef Interaction References