Active-Site Conformational Fluctuations Promote the Enzymatic Activity of NDM-1

Antimicrobial Agents and Chemotherapy
Hongmin ZhangQuan Hao

Abstract

β-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 activit...Continue Reading

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Citations

Jun 7, 2020·Biomolecules·Antonella R PalaciosAlejandro J Vila
Dec 11, 2020·Bioorganic & Medicinal Chemistry·Guixing MaHongmin Zhang
Nov 8, 2020·Clinical Microbiology and Infection : the Official Publication of the European Society of Clinical Microbiology and Infectious Diseases·Vivek Kumar RanjanRanadhir Chakraborty
May 29, 2020·International Journal of Biological Macromolecules·Abid AliAsad U Khan
May 1, 2021·International Journal of Molecular Sciences·Qian-Qian LiDong-Yeul Kwon
Apr 19, 2019·ACS Medicinal Chemistry Letters·Laura CendronDonatella Tondi
Aug 28, 2019·Journal of Medicinal Chemistry·Alen KrajncChristopher J Schofield
Jul 27, 2021·Antimicrobial Agents and Chemotherapy·Carolina LópezAlejandro J Vila
Dec 29, 2021·Journal of Biomolecular Structure & Dynamics·Bipasa KarDebdutta Bhattacharya

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