5YPN

Crystal structure of NDM-1 bound to hydrolyzed meropenem representing an EI2 complex

Summary for 5YPN

• Entry DOI: 10.2210/pdb5ypn/pdb
• Descriptor: Metallo-beta-lactamase NDM-1, ZINC ION, (2~{S},3~{R},4~{S})-2-[(2~{S},3~{R})-1,3-bis(oxidanyl)-1-oxidanylidene-butan-2-yl]-4-[(3~{S},5~{S})-5-(dimethylcarbamoy l)pyrrolidin-3-yl]sulfanyl-3-methyl-3,4-dihydro-2~{H}-pyrrole-5-carboxylic acid, ... (5 entities in total)
• Functional Keywords: mdm-1, meropenem, ei2 complex, hydrolase
• Biological source: Escherichia coli
• Total number of polymer chains: 2
• Total formula weight: 52520.36

Authors

Feng, H.,Liu, W.,Wang, D. (deposition date: 2017-11-02, release date: 2018-02-21, Last modification date: 2023-11-22)

Primary citation

Feng, H.,Liu, X.,Wang, S.,Fleming, J.,Wang, D.C.,Liu, W.
The mechanism of NDM-1-catalyzed carbapenem hydrolysis is distinct from that of penicillin or cephalosporin hydrolysis.
Nat Commun, 8:2242-2242, 2017

PubMed Abstract: New Delhi metallo-β-lactamases (NDMs), the recent additions to metallo-β-lactamases (MBLs), pose a serious public health threat due to its highly efficient hydrolysis of β-lactam antibiotics and rapid worldwide dissemination. The MBL-hydrolyzing mechanism for carbapenems is less studied than that of penicillins and cephalosporins. Here, we report crystal structures of NDM-1 in complex with hydrolyzed imipenem and meropenem, at resolutions of 1.80-2.32 Å, together with NMR spectra monitoring meropenem hydrolysis. Three enzyme-intermediate/product derivatives, EI, EI, and EP, are trapped in these crystals. Our structural data reveal double-bond tautomerization from Δ to Δ, absence of a bridging water molecule and an exclusive β-diastereomeric product, all suggesting that the hydrolytic intermediates are protonated by a bulky water molecule incoming from the β-face. These results strongly suggest a distinct mechanism of NDM-1-catalyzed carbapenem hydrolysis from that of penicillin or cephalosporin hydrolysis, which may provide a novel rationale for design of mechanism-based inhibitors.

PubMed: 29269938
DOI: 10.1038/s41467-017-02339-w

Experimental method

X-RAY DIFFRACTION (2.12 Å)