Active-Site Conformational Fluctuations Promote the Enzymatic Activity of NDM-1.
Antimicrob Agents Chemother
; 62(11)2018 11.
Article
em En
| MEDLINE
| ID: mdl-30150473
ABSTRACT
ß-Lactam antibiotics are the mainstay for the treatment of bacterial infections. However, elevated resistance to these antibiotics mediated by metallo-ß-lactamases (MBLs) has become a global concern. New Delhi metallo-ß-lactamase-1 (NDM-1), a newly added member of the MBL family that can hydrolyze almost all ß-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.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Beta-Lactamases
Limite:
Humans
Idioma:
En
Revista:
Antimicrob Agents Chemother
Ano de publicação:
2018
Tipo de documento:
Article