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Mutation of Gly-11 on the Dimer Interface Results in the Complete Crystallographic Dimer Dissociation of Severe Acute Respiratory Syndrome Coronavirus 3C-like Protease: CRYSTAL STRUCTURE WITH MOLECULAR DYNAMICS SIMULATIONS
SARS-CoV 3C-like protease (3CL(pro)) is an attractive target for anti-severe acute respiratory syndrome (SARS) drug discovery, and its dimerization has been extensively proved to be indispensable for enzymatic activity. However, the reason why the dissociated monomer is inactive still remains unclea...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.
2008
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982321/ https://www.ncbi.nlm.nih.gov/pubmed/17977841 http://dx.doi.org/10.1074/jbc.M705240200 |
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author | Chen, Shuai Hu, Tiancen Zhang, Jian Chen, Jing Chen, Kaixian Ding, Jianping Jiang, Hualiang Shen, Xu |
author_facet | Chen, Shuai Hu, Tiancen Zhang, Jian Chen, Jing Chen, Kaixian Ding, Jianping Jiang, Hualiang Shen, Xu |
author_sort | Chen, Shuai |
collection | PubMed |
description | SARS-CoV 3C-like protease (3CL(pro)) is an attractive target for anti-severe acute respiratory syndrome (SARS) drug discovery, and its dimerization has been extensively proved to be indispensable for enzymatic activity. However, the reason why the dissociated monomer is inactive still remains unclear due to the absence of the monomer structure. In this study, we showed that mutation of the dimer-interface residue Gly-11 to alanine entirely abolished the activity of SARS-CoV 3CL(pro). Subsequently, we determined the crystal structure of this mutant and discovered a complete crystallographic dimer dissociation of SARS-CoV 3CL(pro). The mutation might shorten the α-helix A′ of domain I and cause a mis-oriented N-terminal finger that could not correctly squeeze into the pocket of another monomer during dimerization, thus destabilizing the dimer structure. Several structural features essential for catalysis and substrate recognition are severely impaired in the G11A monomer. Moreover, domain III rotates dramatically against the chymotrypsin fold compared with the dimer, from which we proposed a putative dimerization model for SARS-CoV 3CL(pro). As the first reported monomer structure for SARS-CoV 3CL(pro), the crystal structure of G11A mutant might provide insight into the dimerization mechanism of the protease and supply direct structural evidence for the incompetence of the dissociated monomer. |
format | Online Article Text |
id | pubmed-7982321 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2008 |
publisher | ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology. |
record_format | MEDLINE/PubMed |
spelling | pubmed-79823212021-03-23 Mutation of Gly-11 on the Dimer Interface Results in the Complete Crystallographic Dimer Dissociation of Severe Acute Respiratory Syndrome Coronavirus 3C-like Protease: CRYSTAL STRUCTURE WITH MOLECULAR DYNAMICS SIMULATIONS Chen, Shuai Hu, Tiancen Zhang, Jian Chen, Jing Chen, Kaixian Ding, Jianping Jiang, Hualiang Shen, Xu J Biol Chem Protein Structure and Folding SARS-CoV 3C-like protease (3CL(pro)) is an attractive target for anti-severe acute respiratory syndrome (SARS) drug discovery, and its dimerization has been extensively proved to be indispensable for enzymatic activity. However, the reason why the dissociated monomer is inactive still remains unclear due to the absence of the monomer structure. In this study, we showed that mutation of the dimer-interface residue Gly-11 to alanine entirely abolished the activity of SARS-CoV 3CL(pro). Subsequently, we determined the crystal structure of this mutant and discovered a complete crystallographic dimer dissociation of SARS-CoV 3CL(pro). The mutation might shorten the α-helix A′ of domain I and cause a mis-oriented N-terminal finger that could not correctly squeeze into the pocket of another monomer during dimerization, thus destabilizing the dimer structure. Several structural features essential for catalysis and substrate recognition are severely impaired in the G11A monomer. Moreover, domain III rotates dramatically against the chymotrypsin fold compared with the dimer, from which we proposed a putative dimerization model for SARS-CoV 3CL(pro). As the first reported monomer structure for SARS-CoV 3CL(pro), the crystal structure of G11A mutant might provide insight into the dimerization mechanism of the protease and supply direct structural evidence for the incompetence of the dissociated monomer. ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology. 2008-01-04 2021-01-04 /pmc/articles/PMC7982321/ /pubmed/17977841 http://dx.doi.org/10.1074/jbc.M705240200 Text en © 2008 © 2008 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. |
spellingShingle | Protein Structure and Folding Chen, Shuai Hu, Tiancen Zhang, Jian Chen, Jing Chen, Kaixian Ding, Jianping Jiang, Hualiang Shen, Xu Mutation of Gly-11 on the Dimer Interface Results in the Complete Crystallographic Dimer Dissociation of Severe Acute Respiratory Syndrome Coronavirus 3C-like Protease: CRYSTAL STRUCTURE WITH MOLECULAR DYNAMICS SIMULATIONS |
title | Mutation of Gly-11 on the Dimer Interface Results in the Complete Crystallographic Dimer Dissociation of Severe Acute Respiratory Syndrome Coronavirus 3C-like Protease: CRYSTAL STRUCTURE WITH MOLECULAR DYNAMICS SIMULATIONS |
title_full | Mutation of Gly-11 on the Dimer Interface Results in the Complete Crystallographic Dimer Dissociation of Severe Acute Respiratory Syndrome Coronavirus 3C-like Protease: CRYSTAL STRUCTURE WITH MOLECULAR DYNAMICS SIMULATIONS |
title_fullStr | Mutation of Gly-11 on the Dimer Interface Results in the Complete Crystallographic Dimer Dissociation of Severe Acute Respiratory Syndrome Coronavirus 3C-like Protease: CRYSTAL STRUCTURE WITH MOLECULAR DYNAMICS SIMULATIONS |
title_full_unstemmed | Mutation of Gly-11 on the Dimer Interface Results in the Complete Crystallographic Dimer Dissociation of Severe Acute Respiratory Syndrome Coronavirus 3C-like Protease: CRYSTAL STRUCTURE WITH MOLECULAR DYNAMICS SIMULATIONS |
title_short | Mutation of Gly-11 on the Dimer Interface Results in the Complete Crystallographic Dimer Dissociation of Severe Acute Respiratory Syndrome Coronavirus 3C-like Protease: CRYSTAL STRUCTURE WITH MOLECULAR DYNAMICS SIMULATIONS |
title_sort | mutation of gly-11 on the dimer interface results in the complete crystallographic dimer dissociation of severe acute respiratory syndrome coronavirus 3c-like protease: crystal structure with molecular dynamics simulations |
topic | Protein Structure and Folding |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982321/ https://www.ncbi.nlm.nih.gov/pubmed/17977841 http://dx.doi.org/10.1074/jbc.M705240200 |
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