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Article: Active-site conformational fluctuations promote the enzymatic activity of NDM-1

TitleActive-site conformational fluctuations promote the enzymatic activity of NDM-1
Authors
Issue Date2018
PublisherAmerican Society for Microbiology. The Journal's web site is located at http://aac.asm.org/
Citation
Antimicrobial Agents and Chemotherapy, 2018, v. 62 n. 11, article no. e01579-18 How to Cite?
Abstractβ-Lactam antibiotics are the mainstay for the treatment of bacterial infections. However, elevated resistance to these antibiotics mediated by metallo-β-lactamases (MBLs) has become a global concern. New Delhi metallo-β-lactamase-1 (NDM-1), a newly added member of the MBL family that can hydrolyze almost all β-lactam antibiotics, has rapidly spread all over the world and poses serious clinical threats. Broad-spectrum and mechanism-based inhibitors against all MBLs are highly desired, but the differential mechanisms of MBLs toward different antibiotics pose a great challenge. To facilitate the design of mechanism-based inhibitors, we investigated the active-site conformational changes of NDM-1 through the determination of a series of 15 high-resolution crystal structures in native form and in complex with products and by using biochemical and biophysical studies, site-directed mutagenesis, and molecular dynamics computation. The structural studies reveal the consistency of the active-site conformations in NDM-1/product complexes and the fluctuation in native NDM-1 structures. The enzymatic measurements indicate a correlation between enzymatic activity and the active-site fluctuation, with more fluctuation favoring higher activity. This correlation is further validated by structural and enzymatic studies of the Q123G mutant. Our combinational studies suggest that active-site conformational fluctuation promotes the enzymatic activity of NDM-1, which may guide further mechanism studies and inhibitor design.
Persistent Identifierhttp://hdl.handle.net/10722/261422
ISSN
2017 Impact Factor: 4.256
2015 SCImago Journal Rankings: 2.322
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorZhang, H-
dc.contributor.authorMa, G-
dc.contributor.authorZhu, Y-
dc.contributor.authorZENG, L-
dc.contributor.authorAshmad, A-
dc.contributor.authorWang, C-
dc.contributor.authorPang, B-
dc.contributor.authorFang, H-
dc.contributor.authorZhao, L-
dc.contributor.authorHao, Q-
dc.date.accessioned2018-09-14T08:57:53Z-
dc.date.available2018-09-14T08:57:53Z-
dc.date.issued2018-
dc.identifier.citationAntimicrobial Agents and Chemotherapy, 2018, v. 62 n. 11, article no. e01579-18-
dc.identifier.issn0066-4804-
dc.identifier.urihttp://hdl.handle.net/10722/261422-
dc.description.abstractβ-Lactam antibiotics are the mainstay for the treatment of bacterial infections. However, elevated resistance to these antibiotics mediated by metallo-β-lactamases (MBLs) has become a global concern. New Delhi metallo-β-lactamase-1 (NDM-1), a newly added member of the MBL family that can hydrolyze almost all β-lactam antibiotics, has rapidly spread all over the world and poses serious clinical threats. Broad-spectrum and mechanism-based inhibitors against all MBLs are highly desired, but the differential mechanisms of MBLs toward different antibiotics pose a great challenge. To facilitate the design of mechanism-based inhibitors, we investigated the active-site conformational changes of NDM-1 through the determination of a series of 15 high-resolution crystal structures in native form and in complex with products and by using biochemical and biophysical studies, site-directed mutagenesis, and molecular dynamics computation. The structural studies reveal the consistency of the active-site conformations in NDM-1/product complexes and the fluctuation in native NDM-1 structures. The enzymatic measurements indicate a correlation between enzymatic activity and the active-site fluctuation, with more fluctuation favoring higher activity. This correlation is further validated by structural and enzymatic studies of the Q123G mutant. Our combinational studies suggest that active-site conformational fluctuation promotes the enzymatic activity of NDM-1, which may guide further mechanism studies and inhibitor design.-
dc.languageeng-
dc.publisherAmerican Society for Microbiology. The Journal's web site is located at http://aac.asm.org/-
dc.relation.ispartofAntimicrobial Agents and Chemotherapy-
dc.rightsAntimicrobial Agents and Chemotherapy. Copyright © American Society for Microbiology.-
dc.titleActive-site conformational fluctuations promote the enzymatic activity of NDM-1-
dc.typeArticle-
dc.identifier.emailHao, Q: qhao@hku.hk-
dc.identifier.authorityHao, Q=rp01332-
dc.description.naturepostprint-
dc.identifier.doi10.1128/AAC.01579-18-
dc.identifier.pmid30150473-
dc.identifier.hkuros290900-
dc.identifier.volume62-
dc.identifier.issue11-
dc.identifier.spagee01579-18-
dc.identifier.epagee01579-18-
dc.identifier.isiWOS:000448186900067-
dc.publisher.placeUnited States-

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