Enzymes Pub Date : 2021-01-01 Epub Date: 2021-07-24 DOI: 10.1016/bs.enz.2021.06.008

Pu Chen, Zhijian Li, Sheng Cui

{"title":"Picornaviral 2C proteins: A unique ATPase family critical in virus replication.","authors":"Pu Chen, Zhijian Li, Sheng Cui","doi":"10.1016/bs.enz.2021.06.008","DOIUrl":"https://doi.org/10.1016/bs.enz.2021.06.008","url":null,"abstract":"The 2C proteins of Picornaviridae are unique members of AAA+ protein family. Although picornavirus 2C shares many conserved motifs with Super Family 3 DNA helicases, duplex unwinding activity of many 2C proteins remains undetected, and high-resolution structures of 2C hexamers are unavailable. All characterized 2C proteins exhibit ATPase activity, but the purpose of ATP hydrolysis is not fully understood. 2C is highly conserved among picornaviruses and plays crucial roles in nearly all steps of the virus lifecycle. It is therefore considered as an effective target for broad-spectrum antiviral drug development. Crystallographic investigation of enterovirus 2C proteins provide structural details important for the elucidation of 2C function and development of antiviral drugs. This chapter summarizes not only the findings of enzymatic activities, biochemical and structural characterizations of the 2C proteins, but also their role in virus replication, immune evasion and morphogenesis. The linkage between structure and function of the 2C proteins is discussed in detail. Inhibitors targeting the 2C proteins are also summarized to provide an overview of drug development. Finally, we raise several key questions to be addressed in this field and provide future research perspective on this unique class of ATPases.","PeriodicalId":39097,"journal":{"name":"Enzymes","volume":" ","pages":"235-264"},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39569532","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: 1

Retroviral integrase: Structure, mechanism, and inhibition. 逆转录病毒整合酶:结构、机制和抑制。

Enzymes Pub Date : 2021-01-01 Epub Date: 2021-08-23 DOI: 10.1016/bs.enz.2021.06.007

Dario Oliveira Passos, Min Li, Robert Craigie, Dmitry Lyumkis

引用次数: 5

DNA polymerases of herpesviruses and their inhibitors. 疱疹病毒的DNA聚合酶及其抑制剂。

Enzymes Pub Date : 2021-01-01 Epub Date: 2021-09-01 DOI: 10.1016/bs.enz.2021.07.003

Jocelyne Piret, Guy Boivin

{"title":"DNA polymerases of herpesviruses and their inhibitors.","authors":"Jocelyne Piret, Guy Boivin","doi":"10.1016/bs.enz.2021.07.003","DOIUrl":"https://doi.org/10.1016/bs.enz.2021.07.003","url":null,"abstract":"Human herpesviruses are large double-stranded DNA viruses belonging to the Herpesviridae family. The main characteristics of these viruses are their ability to establish a lifelong latency into the host with a potential to reactivate periodically. Primary infections and reactivations with herpesviruses are responsible for a large spectrum of diseases and may result in severe complications in immunocompromised patients. The viral DNA polymerase is a key enzyme in the replicative cycle of herpesviruses, and the target of most antiviral agents (i.e., nucleoside, nucleotide and pyrophosphate analogs). However, long-term prophylaxis and treatment with these antivirals may lead to the emergence of drug-resistant isolates harboring mutations in genes encoding viral enzymes that phosphorylate drugs (nucleoside analogs) and/or DNA polymerases, with potential cross-resistance between the different analogs. Drug resistance mutations mainly arise in conserved regions of the polymerase and exonuclease functional domains of these enzymes. In the polymerase domain, mutations associated with resistance to nucleoside/nucleotide analogs may directly or indirectly affect drug binding or incorporation into the primer strand, or increase the rate of extension of DNA to overcome chain termination. In the exonuclease domain, mutations conferring resistance to nucleoside/nucleotide analogs may reduce the rate of excision of incorporated drug, or continue DNA elongation after drug incorporation without excision. Mutations associated with resistance to pyrophosphate analogs may alter drug binding or the conformational changes of the polymerase domain required for an efficient activity of the enzyme. Novel herpesvirus inhibitors with a potent antiviral activity against drug-resistant isolates are thus needed urgently.","PeriodicalId":39097,"journal":{"name":"Enzymes","volume":" ","pages":"79-132"},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39958017","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: 3

Retroviral reverse transcriptase: Structure, function and inhibition. 逆转录酶:结构、功能和抑制作用。

Enzymes Pub Date : 2021-01-01 Epub Date: 2021-07-24 DOI: 10.1016/bs.enz.2021.06.006

Nicolas Sluis-Cremer

引用次数: 2

In vitro single-molecule manipulation studies of viral DNA replication. 病毒DNA复制的体外单分子操作研究。

Enzymes Pub Date : 2021-01-01 Epub Date: 2021-10-13 DOI: 10.1016/bs.enz.2021.09.001

Rebeca Bocanegra, Ismael Plaza G A, Borja Ibarra

引用次数: 1

Structure and function of negative-strand RNA virus polymerase complexes. 负链RNA病毒聚合酶复合物的结构和功能。

Enzymes Pub Date : 2021-01-01 Epub Date: 2021-11-10 DOI: 10.1016/bs.enz.2021.09.002

Jesse D Pyle, Sean P J Whelan, Louis-Marie Bloyet

引用次数: 5

Structure and function of the poxvirus transcription machinery. 痘病毒转录机制的结构和功能。

Enzymes Pub Date : 2021-01-01 Epub Date: 2021-07-24 DOI: 10.1016/bs.enz.2021.06.005

Utz Fischer, Julia Bartuli, Clemens Grimm

引用次数: 4

Herpesvirus DNA polymerase: Structures, functions, and mechanisms. 疱疹病毒DNA聚合酶:结构、功能和机制。

Enzymes Pub Date : 2021-01-01 Epub Date: 2021-11-02 DOI: 10.1016/bs.enz.2021.09.003

Donald M Coen, Jessica L Lawler, Jonathan Abraham

{"title":"Herpesvirus DNA polymerase: Structures, functions, and mechanisms.","authors":"Donald M Coen, Jessica L Lawler, Jonathan Abraham","doi":"10.1016/bs.enz.2021.09.003","DOIUrl":"https://doi.org/10.1016/bs.enz.2021.09.003","url":null,"abstract":"Herpesviruses comprise a family of DNA viruses that cause a variety of human and veterinary diseases. During productive infection, mammalian, avian, and reptilian herpesviruses replicate their genomes using a set of conserved viral proteins that include a two subunit DNA polymerase. This enzyme is both a model system for family B DNA polymerases and a target for inhibition by antiviral drugs. This chapter reviews the structure, function, and mechanisms of the polymerase of herpes simplex viruses 1 and 2 (HSV), with only occasional mention of polymerases of other herpesviruses such as human cytomegalovirus (HCMV). Antiviral polymerase inhibitors have had the most success against HSV and HCMV. Detailed structural information regarding HSV DNA polymerase is available, as is much functional information regarding the activities of the catalytic subunit (Pol), which include a DNA polymerization activity that can utilize both DNA and RNA primers, a 3'-5' exonuclease activity, and other activities in DNA synthesis and repair and in pathogenesis, including some remaining to be biochemically defined. Similarly, much is known regarding the accessory subunit, which both resembles and differs from sliding clamp processivity factors such as PCNA, and the interactions of this subunit with Pol and DNA. Both subunits contribute to replication fidelity (or lack thereof). The availability of both pharmacologic and genetic tools not only enabled the initial identification of Pol and the pol gene, but has also helped dissect their functions. Nevertheless, important questions remain for this long-studied enzyme, which is still an attractive target for new drug discovery.","PeriodicalId":39097,"journal":{"name":"Enzymes","volume":" ","pages":"133-178"},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39943078","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

Development of EHop-016: a small molecule inhibitor of Rac. 小分子Rac抑制剂EHop-016的研制

Enzymes Pub Date : 2013-01-01 Epub Date: 2013-08-08 DOI: 10.1016/B978-0-12-416749-0.00006-3

Suranganie Dharmawardhane, Eliud Hernandez, Cornelis Vlaar

{"title":"Development of EHop-016: a small molecule inhibitor of Rac.","authors":"Suranganie Dharmawardhane, Eliud Hernandez, Cornelis Vlaar","doi":"10.1016/B978-0-12-416749-0.00006-3","DOIUrl":"https://doi.org/10.1016/B978-0-12-416749-0.00006-3","url":null,"abstract":"The Rac inhibitor EHop-016 was developed as a compound with the potential to inhibit cancer metastasis. Inhibition of the first step of metastasis, migration, is an important strategy for metastasis prevention. The small GTPase Rac acts as a pivotal binary switch that is turned \"on\" by guanine nucleotide exchange factors (GEFs) via a myriad of cell surface receptors, to regulate cancer cell migration, survival, and proliferation. Unlike the related GTPase Ras, Racs are not usually mutated, but overexpressed or overactivated in cancer. Therefore, a rational Rac inhibitor should block the activation of Rac by its upstream effectors, GEFs, and the Rac inhibitor NSC23766 was developed using this rationale. However, this compound is ineffective at inhibiting the elevated Rac activity of metastatic breast cancer cells. Therefore, a panel of small molecule compounds were derived from NSC23766 and screened for Rac activity inhibition in metastatic cancer cells. EHop-016 was identified as a compound that blocks the interaction of Rac with the GEF Vav in metastatic human breast cancer cells with an IC50 of ~1μM. At higher concentrations (10μM), EHop-016 inhibits the related Rho GTPase Cdc42, but not Rho, and also reduces cell viability. Moreover, EHop-016 inhibits the activation of the Rac downstream effector p21-activated kinase, extension of motile actin-based structures, and cell migration. Future goals are to develop EHop-016 as a therapeutic to inhibit cancer metastasis, either individually or in combination with current anticancer compounds. The next generation of EHop-016-based Rac inhibitors is also being developed. ","PeriodicalId":39097,"journal":{"name":"Enzymes","volume":" ","pages":"117-46"},"PeriodicalIF":0.0,"publicationDate":"2013-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/B978-0-12-416749-0.00006-3","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32510932","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: 23

NMR study to identify a ligand-binding pocket in Ras. 核磁共振研究在Ras中鉴定配体结合袋。

Enzymes Pub Date : 2013-01-01 Epub Date: 2013-08-08 DOI: 10.1016/B978-0-12-416749-0.00002-6

Till Maurer, Weiru Wang

{"title":"NMR study to identify a ligand-binding pocket in Ras.","authors":"Till Maurer, Weiru Wang","doi":"10.1016/B978-0-12-416749-0.00002-6","DOIUrl":"https://doi.org/10.1016/B978-0-12-416749-0.00002-6","url":null,"abstract":"Despite decades of intense drug discovery efforts, to date no small molecules have been described that directly bind to Ras protein and effectively antagonize its function. In order to identify and characterize small-molecule binders to KRas, we carried out a fragment-based lead discovery effort. A ligand-detected primary nuclear magnetic resonance (NMR) screen identified 266 fragments from a library of 3285 diverse compounds. Protein-detected NMR using isotopically labeled KRas protein was applied for hit validation and binding site characterization. An area on the KRas surface emerged as a consensus site of fragment binding. X-ray crystallography studies on a subset of the hits elucidated atomic details of the ligand-protein interactions, and revealed that the consensus site comprises a shallow hydrophobic pocket. Comparison among the crystal structures indicated that the ligand-binding pocket is flexible and can be expanded upon ligand binding. The identified ligand-binding pocket is proximal to the protein-protein interface and therefore has the potential to mediate functional effects. Indeed, some ligands inhibited SOS1-dependent nucleotide exchange, although with weak potency. Several Ras ligands have been published in literature, the majority of which were discovered using NMR-based methods. Mapping of the ligand-binding sites revealed five areas on Ras with a high propensity for ligand binding and the potential of modulating Ras activity. ","PeriodicalId":39097,"journal":{"name":"Enzymes","volume":" ","pages":"15-39"},"PeriodicalIF":0.0,"publicationDate":"2013-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/B978-0-12-416749-0.00002-6","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32513118","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: 7

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