5ZGV

Crystal structure of NDM-1 at pH8.0 (Tris) with 2 molecules per asymmetric unit

Summary for 5ZGV

• Entry DOI: 10.2210/pdb5zgv/pdb
• Related: 5X6P 5ZGI 5ZGT 5ZGU
• Descriptor: Metallo-beta-lactamase type 2, ZINC ION, HYDROXIDE ION, ... (5 entities in total)
• Functional Keywords: ndm-1, metallo-beta-lactamase, antibiotic resistent, conformational change, hydrolase
• Biological source: Klebsiella pneumoniae
• Total number of polymer chains: 2
• Total formula weight: 51651.38

Authors

Zhang, H.,Hao, Q. (deposition date: 2018-03-10, release date: 2018-08-22, Last modification date: 2023-11-22)

Primary citation

Zhang, H.,Ma, G.,Zhu, Y.,Zeng, L.,Ahmad, A.,Wang, C.,Pang, B.,Fang, H.,Zhao, L.,Hao, Q.
Active-Site Conformational Fluctuations Promote the Enzymatic Activity of NDM-1.
Antimicrob. Agents Chemother., 62:-, 2018

PubMed 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 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.

PubMed: 30150473
DOI: 10.1128/AAC.01579-18

Experimental method

X-RAY DIFFRACTION (1.15 Å)