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1 online resource (370 p.) |
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Issn Ser |
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Issn Ser
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| Contents |
Intro -- Viral Replication Enzymes and their Inhibitors Part A -- Copyright -- Contents -- Contributors -- Preface -- Chapter One: CoV-er all the bases: Structural perspectives of SARS-CoV-2 RNA synthesis -- 1. Introduction -- 2. Coronavirus genome organization -- 2.1. Continuous and discontinuous RNA synthesis -- 2.2. Subcellular compartmentalization of replication and transcription -- 3. The RNA-dependent RNA polymerase -- 3.1. The holo-RdRp, the central enzyme for replication/transcription -- 3.2. The RdRp active site -- 3.3. The replication/transcription complex -- 3.4. The nsp12-NiRAN domain -- 4. Concerted enzymatic functions vital to replication/transcription -- 4.1. Proofreading and nsp14 ExoN activity -- 4.2. Nsp13: An essential CoV helicase -- 4.3. Template switching and helicase function -- 4.4. RNA capping -- 5. Antivirals targeting the RdRp -- 5.1. Remdesivir -- 5.2. Favipiravir -- 6. Conclusion -- References -- Chapter Two: Mechanisms of inhibition of viral RNA replication by nucleotide analogs -- 1. Mechanistic basis for effective inhibition -- 2. Incorporation versus excision of nucleotide analogs -- 3. Toxicity -- 4. SARS CoV-2 RdRp kinetics and mechanism -- 5. Structural basis for delayed inhibition by Remdesivir -- 6. Role of the proofreading exonuclease in effectiveness of nucleotide analogs -- 7. Summary and future directions -- References -- Chapter Three: HCV RdRp, sofosbuvir and beyond -- 1. Introduction -- 2. Part I: HCV RdRp biochemistry, structure biology, and modulation by viral and human proteins -- 2.1. HCV and NS5B -- 2.2. Biochemical characterization of full-length NS5B -- 2.3. Mutation and deletion studies of HCV NS5B -- 2.4. Characterization of C-terminal truncated HCV NS5BDeltaC21 and NS5BDeltaC55 -- 2.5. Oligomerization of HCV NS5B -- 2.6. Modulation of HCV NS5B by other viral proteins, host factors, and GTP |
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2.7. HCV NS5B-catalyzed de novo and primer-dependent RNA synthesis -- 2.8. X-ray crystal structures of HCV NS5B -- 2.9. NTP-mediated nucleotide excision activity of HCV NS5B -- 3. Part II: HCV drug discovery targeting HCV NS5B -- 3.1. HCV RdRp ternary complex with nucleotide inhibitors -- 3.2. Toxicity and off-target evaluation -- 3.3. Beyond HCV drug discovery into emerging viruses -- References -- Chapter Four: Understanding viral replication and transcription using single-molecule techniques -- 1. Introduction -- 1.1. Single-molecule Förster resonance energy transfer -- 1.2. Optical tweezers -- 1.3. Magnetic tweezers -- 1.4. Flow-stretching -- 1.5. Atomic force microscopy -- 1.6. Alternative approaches -- 2. Single-molecule FRET of influenza A virus RNA synthesis -- 2.1. Influenza A virus RNA synthesis -- 2.2. Promoter binding by the IAV RNA polymerase -- 2.3. Transition from pre-initiation to initiation of the IAV RNA polymerase -- 3. Single-molecule analysis of HIV-I reverse transcriptase activity -- 3.1. HIV-I infection and reverse transcription -- 3.2. Observing reserve transcriptase activity using smFRET -- 4. Analysis of hepatitis C virus RNA and helicase function -- 4.1. The HCV protein and RNA synthesis -- 4.2. HCV IRES structure and function -- 4.3. Determining the step size of the HCV NS3 helicase -- 5. Single-molecule observation of DNA phage replication -- 5.1. Diverse replication and transcription mechanisms of bacteriophages -- 5.2. Exonuclease activity of phage lambda -- 5.3. Leading- and lagging-strand synthesis by T7 replicase -- 6. Single-molecule analysis of polymerase fidelity -- 6.1. Polymerase nucleotide misincorporation -- 6.2. Pausing and fidelity of the bacteriophage Phi6 polymerase P2 -- 6.3. Fidelity and nucleoside analog incorporation by poliovirus polymerase 3D -- 7. Conclusions -- Acknowledgments |
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Competing interests -- References -- Chapter Five: In vitro single-molecule manipulation studies of viral DNA replication -- 1. Introduction -- 2. In vitro single molecule manipulation methods: Optical and magnetic tweezers -- 2.1. Optical tweezers -- 2.2. Magnetic tweezers -- 2.3. Detection of activity -- 3. Mechanical properties of single- and double-stranded DNA -- 4. Manipulation of single SSB-ssDNA complexes -- 5. Mechanical tension as a variable to study the real-time kinetics of primer extension DNA synthesis -- 6. Mechanical force and mechano-chemistry: Identification of the translocation step of DNA polymerases -- 7. Mechanical tension as a variable to study strand displacement DNA synthesis -- 8. Mechanical tension as a variable to study DNA unwinding by helicases -- 9. When the helicase has company: Mechanical manipulation of several proteins at the fork -- 10. Summary and conclusions -- Acknowledgments -- References -- Chapter Six: Allosteric and dynamic control of RNA-dependent RNA polymerase function and fidelity -- 1. Brief introduction to the structure and function of RNA-dependent RNA polymerases -- 1.1. RNA-dependent RNA polymerase fidelity as a key aspect of virus biology -- 1.2. Allostery and dynamics in RNA-dependent RNA polymerase function -- 2. NMR and MD methods to evaluate protein structure and dynamics -- 2.1. NMR spectra provide insight into protein conformational changes -- 2.2. Following RNA and NTP titrations in PV RdRp using NMR -- 2.3. NMR relaxation methods provide insight into conformational dynamics across multiple timescales -- 2.4. Molecular dynamics simulations can provide movies of protein conformational dynamics -- 3. Protein conformational dynamics in the catalytic cycle of RNA-dependent RNA polymerases -- 3.1. Slow and fast dynamics in the cystoviral 6 bacteriophage RdRp |
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3.2. Fast dynamics in the cystoviral 12 bacteriophage P2 RdRp -- 3.3. Fast and slow dynamics in PV RdRp in the absence of RNA and nucleotides -- 4. Dynamics and allostery important for the fidelity of nucleotide incorporation -- 4.1. Loop dynamics re-position the motif-D lysine for general acid catalysis -- 4.2. Rational approaches to modifying RdRp dynamics and function -- 4.3. Remote substitutions alter RdRp fidelity and protein conformational dynamics -- 4.4. Triphosphate reorientation as a fidelity checkpoint in RdRps -- 4.5. A model for nucleotide discrimination in RdRps -- 5. Dynamics and allostery important for anti-viral drug development -- 5.1. Allosteric non-nucleoside inhibitors disrupt dynamics in HCV RdRp -- 5.2. 2-C-methylated nucleotides prevent active site closure of the RNA-dependent RNA polymerase -- 6. Conclusions -- Acknowledgments -- References -- Chapter Seven: Single-cell analysis for the study of viral inhibitors -- 1. Introduction -- 2. Microfluidics: A powerful tool for single-cell virology -- 3. Study of antivirals at single-cell resolution -- 4. Viral transmission dynamics at the single-cell level -- 5. Future of single-cell virology -- Acknowledgments -- References -- Chapter Eight: Structural basis of viral RNA-dependent RNA polymerase nucleotide addition cycle in picornaviruses -- 1. Introduction -- 2. Structural basis of picornaviral RdRP NAC -- 2.1. Structures of picornavirus RdRPs -- 2.2. The reference viral RdRP NAC states illustrated in PV and EV71 -- 2.3. A ̀̀two-steṕ́ induced fit in RdRP active site closure -- 2.4. A motif G-mediated stringent control of RdRP translocation in an asymmetric manner -- 3. Perspective -- References -- Chapter Nine: Picornaviral 2C proteins: A unique ATPase family critical in virus replication -- 1. Introduction -- 2. The function of picornaviral 2C protein |
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2.1. Conserved domains/motifs -- 2.2. ATPase and helicase activities -- 3. RNA binding activity -- 4. The roles of picornaviral 2C protein in the virus lifecycle -- 4.1. Role in replication -- 4.2. Role in immune evasion -- 4.3. Role in morphogenesis -- 5. Structural characterizations of picornaviral 2C protein -- 5.1. Electron microscopy imaging of hexameric ring-like structure -- 5.2. Crystallographic studies -- 5.3. Hexameric ring-like model of 2C proteins -- 6. Inhibitors of picornaviral 2C protein -- 7. Perspectives -- References -- Chapter Ten: Flavivirus enzymes and their inhibitors -- 1. Introduction -- 2. Flavivirus replication -- 2.1. Viral genome organization -- 2.2. Flavivirus life cycle -- 2.3. Flavivirus replication -- 2.4. Inhibitors targeting viral replication -- 3. Flavivirus NS3 protein -- 3.1. NS2B-NS3 protease: Structure and function -- 3.2. Inhibitors of NS2B-NS3 protease -- 3.2.1. Peptide-based inhibitors targeting the active site of NS2B-NS3 protease -- 3.2.2. Small molecule inhibitors targeting the NS2B-NS3 protease active site -- 3.2.3. Inhibitors targeting NS2B and NS3 interaction sites or allosteric sites -- 3.3. NS3 helicase: Structure and function -- 3.4. Inhibitors of NS3 helicase -- 3.4.1. Inhibitors targeting the active site of NS3 helicase -- 3.4.2. Inhibitors targeting allosteric sites of NS3 helicase -- 4. Flavivirus NS5 protein -- 4.1. NS5 methyltransferase: Structure and function -- 4.2. Inhibitors targeting NS5 methyltransferase -- 4.2.1. Inhibitors targeting the active site of NS5 methyltransferase -- 4.2.2. Inhibitors targeting allosteric sites of NS5 methyltransferase -- 4.3. NS5 RNA-dependent RNA polymerase: Structure and function -- 4.4. Inhibitors of NS5 RNA polymerase -- 4.4.1. Nucleoside inhibitors targeting the active site of NS5 polymerase -- 4.4.2. Non-nucleoside inhibitors targeting NS5 polymerase |
| Notes |
Description based upon print version of record |
| Subject |
Virus-induced enzymes.
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Virus-induced enzymes
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| Form |
Electronic book
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| Author |
Arnold, Jamie J
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| ISBN |
9780128234693 |
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0128234695 |
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