Enzymes最新文献_第5页

Retroviral RNase H: Structure, mechanism, and inhibition. 逆转录病毒RNase H:结构、机制和抑制。

Enzymes Pub Date : 2021-01-01 Epub Date: 2021-09-24 DOI: 10.1016/bs.enz.2021.07.007

Tatiana V Ilina, Teresa Brosenitsch, Nicolas Sluis-Cremer, Rieko Ishima

引用次数: 3

Flavivirus enzymes and their inhibitors. 黄病毒酶及其抑制剂。

Enzymes Pub Date : 2021-01-01 Epub Date: 2021-09-01 DOI: 10.1016/bs.enz.2021.07.006

Ekaterina Knyazhanskaya, Marc C Morais, Kyung H Choi

{"title":"Flavivirus enzymes and their inhibitors.","authors":"Ekaterina Knyazhanskaya, Marc C Morais, Kyung H Choi","doi":"10.1016/bs.enz.2021.07.006","DOIUrl":"https://doi.org/10.1016/bs.enz.2021.07.006","url":null,"abstract":"Flaviviruses such as dengue, Japanese encephalitis, West Nile, Yellow Fever and Zika virus, cause viral hemorrhagic fever and encephalitis in humans. However, antiviral therapeutics to treat or prevent flavivirus infections are not yet available. Thus, there is pressing need to develop therapeutics and vaccines that target flavivirus infections. All flaviviruses carry a positive-sense single-stranded RNA genome, which encodes ten proteins; three structural proteins form the virus shell, and seven nonstructural (NS) proteins are involved in replication of the viral genome. While all NS proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) are part of a functional membrane-bound replication complex, enzymatic activities required for flaviviral replication reside in only two NS proteins, NS3 and NS5. NS3 functions as a protease, helicase, and triphosphatase, and NS5 as a capping enzyme, methyltransferase, and RNA-dependent RNA polymerase. In this chapter, we provide an overview of viral replication focusing on the structure and function of NS3 and NS5 replicases. We further describe strategies and examples of current efforts to identify potential flavivirus inhibitors against NS3 and NS5 enzymatic activities that can be developed as therapeutic agents to combat flavivirus infections.","PeriodicalId":39097,"journal":{"name":"Enzymes","volume":" ","pages":"265-303"},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8717743/pdf/nihms-1765121.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39560060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 13

Understanding viral replication and transcription using single-molecule techniques. 利用单分子技术了解病毒复制和转录。

Enzymes Pub Date : 2021-01-01 Epub Date: 2021-09-23 DOI: 10.1016/bs.enz.2021.07.005

Emmanuelle Pitre, Aartjan J W Te Velthuis

引用次数: 0

Watching the bacterial RNA polymerase transcription reaction by time-dependent soak-trigger-freeze X-ray crystallography. 用时间依赖性浸泡-触发-冷冻x射线晶体学观察细菌RNA聚合酶转录反应。

Enzymes Pub Date : 2021-01-01 Epub Date: 2021-07-24 DOI: 10.1016/bs.enz.2021.06.009

Yeonoh Shin, Katsuhiko S Murakami

引用次数: 1

HCV RdRp, sofosbuvir and beyond. HCV RdRp，索非布韦及其他。

Enzymes Pub Date : 2021-01-01 Epub Date: 2021-09-24 DOI: 10.1016/bs.enz.2021.06.003

Joy Y Feng, Adrian S Ray

{"title":"HCV RdRp, sofosbuvir and beyond.","authors":"Joy Y Feng, Adrian S Ray","doi":"10.1016/bs.enz.2021.06.003","DOIUrl":"https://doi.org/10.1016/bs.enz.2021.06.003","url":null,"abstract":"The therapeutic targeting of the nonstructural protein 5B (NS5B) RNA-dependent RNA polymerase (RdRp) of the Hepatitis C Virus (HCV) with nucleotide analogs led to a deep understanding of this enzymes structure, function and substrate specificity. Unlike previously studied DNA polymerases including the reverse transcriptase of Human Immunodeficiency Virus, development of biochemical assays for HCV RdRp proved challenging due to low solubility of the full-length protein and inefficient acceptance of exogenous primer/templates. Despite the poor apparent specific activity, HCV RdRp was found to support rapid and processive transcription once elongation is initiated in vitro consistent with its high level of viral replication in the livers of patients. Understanding of the substrate specificity of HCV RdRp led to the discovery of the active triphosphate of sofosbuvir as a nonobligate chain-terminator of viral RNA transcripts. The ternary crystal structure of HCV RdRp, primer/template, and incoming nucleotide showed the interaction between the nucleotide analog and the 2'-hydroxyl binding pocket and how an unfit mutation of serine 282 to threonine results in resistance by interacting with the uracil base and modified 2'-position of the analog. Host polymerases mediate off-target toxicity of nucleotide analogs and the active metabolite of sofosbuvir was found to not be efficiently incorporated by host polymerases including the mitochondrial RNA polymerase (POLRMT). Knowledge from studying inhibitors of HCV RdRp serves to advance antiviral drug discovery for other emerging RNA viruses including the discovery of remdesivir as an inhibitor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), the virus that causes COVID-19.","PeriodicalId":39097,"journal":{"name":"Enzymes","volume":" ","pages":"63-82"},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39560062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 5

Viral genome packaging machines: Structure and enzymology. 病毒基因组包装机：结构和酶学。

Enzymes Pub Date : 2021-01-01 Epub Date: 2021-11-10 DOI: 10.1016/bs.enz.2021.09.006

Carlos E Catalano, Marc C Morais

引用次数: 0

Mechanisms of inhibition of viral RNA replication by nucleotide analogs. 核苷酸类似物抑制病毒RNA复制的机制。

Enzymes Pub Date : 2021-01-01 Epub Date: 2021-09-27 DOI: 10.1016/bs.enz.2021.07.001

Kenneth A Johnson, Tyler Dangerfield

引用次数: 7

Allosteric and dynamic control of RNA-dependent RNA polymerase function and fidelity. RNA依赖性RNA聚合酶功能和保真度的变构和动态控制。

Enzymes Pub Date : 2021-01-01 Epub Date: 2021-07-19 DOI: 10.1016/bs.enz.2021.06.001

Dennis S Winston, David D Boehr

{"title":"Allosteric and dynamic control of RNA-dependent RNA polymerase function and fidelity.","authors":"Dennis S Winston, David D Boehr","doi":"10.1016/bs.enz.2021.06.001","DOIUrl":"https://doi.org/10.1016/bs.enz.2021.06.001","url":null,"abstract":"All RNA viruses encode an RNA-dependent RNA polymerase (RdRp) responsible for genome replication. It is now recognized that enzymes in general, and RdRps specifically, are dynamic macromolecular machines such that their moving parts, including active site loops, play direct functional roles. While X-ray crystallography has provided deep insight into structural elements important for RdRp function, this methodology generally provides only static snapshots, and so is limited in its ability to report on dynamic fluctuations away from the lowest energy conformation. Nuclear magnetic resonance (NMR), molecular dynamics (MD) simulations and other biophysical techniques have brought new insight into RdRp function by their ability to characterize the trajectories, kinetics and thermodynamics of conformational motions. In particular, these methodologies have identified coordinated motions among conserved structural motifs necessary for nucleotide selection and incorporation. Disruption of these motions through amino acid substitutions or inhibitor binding impairs RdRp function. Understanding and re-engineering these motions thus provides exciting new avenues for anti-viral strategies. This chapter outlines the basics of these methodologies, summarizes the dynamic motions observed in different RdRps important for nucleotide selection and incorporation, and illustrates how this information can be leveraged towards rational vaccine strain development and anti-viral drug design.","PeriodicalId":39097,"journal":{"name":"Enzymes","volume":" ","pages":"149-193"},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39569529","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Structural basis of viral RNA-dependent RNA polymerase nucleotide addition cycle in picornaviruses. 小核糖核酸病毒RNA依赖RNA聚合酶核苷酸加成周期的结构基础。

Enzymes Pub Date : 2021-01-01 Epub Date: 2021-07-19 DOI: 10.1016/bs.enz.2021.06.002

Peng Gong

引用次数: 6

Single-cell analysis for the study of viral inhibitors. 用于病毒抑制剂研究的单细胞分析。

Enzymes Pub Date : 2021-01-01 Epub Date: 2021-08-23 DOI: 10.1016/bs.enz.2021.07.004

Mohamad S Sotoudegan, Jamie J Arnold, Craig E Cameron

{"title":"Single-cell analysis for the study of viral inhibitors.","authors":"Mohamad S Sotoudegan, Jamie J Arnold, Craig E Cameron","doi":"10.1016/bs.enz.2021.07.004","DOIUrl":"https://doi.org/10.1016/bs.enz.2021.07.004","url":null,"abstract":"Stochastic outcomes of viral infections are attributed in large part to multiple layers of intrinsic and extrinsic heterogeneity that exist within a population of cells and viruses. Traditional methods in virology often lack the ability to demonstrate cell-to-cell variability in response to the invasion of viruses, and to decipher the sources of heterogeneities that are reflected in the variable infection dynamics. To overcome this challenge, the field of single-cell virology emerged less than a decade ago, enabling researchers to reveal the behavior of single, isolated, infected cells that has been masked in population-based assays. The use of microfluidics in single-cell virology, in particular, has resulted in the development of high-throughput devices that are capable of capturing, isolating, and monitoring single infected cells over the duration of an infection. Results from the studies of viral infection dynamics presented in this chapter indicate how single-cell data provide a more accurate prediction of the start time, replication rate, duration, and yield of infection when compared to population-based data. Additionally, single-cell analysis reveals striking differences between genetically distinct viruses that are almost indistinguishable in population methods. Importantly, both the efficacy and distinct mechanisms of action of antiviral compounds can be elucidated by using single-cell analysis.","PeriodicalId":39097,"journal":{"name":"Enzymes","volume":" ","pages":"195-213"},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39569530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0