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Unraveling the catalytic mechanism of SARS-CoV-2 papain-like protease with allosteric modulation of C270 mutation using multiscale computational approaches

文献类型：期刊论文

作者Shao, Qiang3,4; Xiong, Muya3,4; Li, Jiameng2; Hu, Hangchen1; Su, Haixia4; Xu, Yechun1,2,3,4
刊名CHEMICAL SCIENCE
出版日期2023-05-10
卷号14期号:18页码:4681-4696
DOI10.1039/d3sc00166k
文献子类Article
英文摘要Papain-like protease (PLpro) is a promising therapeutic target against SARS-CoV-2, but its restricted S1/S2 subsites pose an obstacle in developing active site-directed inhibitors. We have recently identified C270 as a novel covalent allosteric site for SARS-CoV-2 PLpro inhibitors. Here we present a theoretical investigation of the proteolysis reaction catalyzed by the wild-type SARS-CoV-2 PLpro as well as the C270R mutant. Enhanced sampling MD simulations were first performed to explore the influence of C270R mutation on the protease dynamics, and sampled thermodynamically favorable conformations were then submitted to MM/PBSA and QM/MM MD simulations for thorough characterization of the protease-substrate binding and covalent reactions. The disclosed proteolysis mechanism of PLpro, as characterized by the occurrence of proton transfer from the catalytic C111 to H272 prior to the substrate binding and with deacylation being the rate-determining step of the whole proteolysis process, is not completely identical to that of the 3C-like protease, another key cysteine protease of coronaviruses. The C270R mutation alters the structural dynamics of the BL2 loop that indirectly impairs the catalytic function of H272 and reduces the binding of the substrate with the protease, ultimately showing an inhibitory effect on PLpro. Together, these results provide a comprehensive understanding at the atomic level of the key aspects of SARS-CoV-2 PLpro proteolysis, including the catalytic activity allosterically regulated by C270 modification, which is crucial to the follow-up inhibitor design and development.
WOS关键词RESPIRATORY SYNDROME CORONAVIRUS ; MOLECULAR-DYNAMICS SIMULATIONS ; SELECTIVE INHIBITORS ; SIDE-CHAIN ; QM/MM ; CYSTEINE ; BINDING ; IMPLEMENTATION ; PATHWAY ; POTENT
WOS研究方向Chemistry
语种英语
WOS记录号WOS:000974604400001
出版者ROYAL SOC CHEMISTRY
源URL[http://119.78.100.183/handle/2S10ELR8/309646]  
专题新药研究国家重点实验室
通讯作者Shao, Qiang; Xu, Yechun
作者单位1.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
2.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China;
3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China;
4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China;
推荐引用方式
GB/T 7714		 Shao, Qiang,Xiong, Muya,Li, Jiameng,et al. Unraveling the catalytic mechanism of SARS-CoV-2 papain-like protease with allosteric modulation of C270 mutation using multiscale computational approaches[J]. CHEMICAL SCIENCE,2023,14(18):4681-4696.
APA Shao, Qiang,Xiong, Muya,Li, Jiameng,Hu, Hangchen,Su, Haixia,&Xu, Yechun.(2023).Unraveling the catalytic mechanism of SARS-CoV-2 papain-like protease with allosteric modulation of C270 mutation using multiscale computational approaches.CHEMICAL SCIENCE,14(18),4681-4696.
MLA Shao, Qiang,et al."Unraveling the catalytic mechanism of SARS-CoV-2 papain-like protease with allosteric modulation of C270 mutation using multiscale computational approaches".CHEMICAL SCIENCE 14.18(2023):4681-4696.

入库方式： OAI收割

来源：上海药物研究所

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