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Publication Abstract from PubMed

IMP-type metallo-beta-lactamases confer resistance to carbapenems and a broad spectrum of beta-lactam antibiotics. IMP-6 and IMP-1 differ by only a point mutation: Ser262 in IMP-1 and Gly262 in IMP-6. The kcat/Km values of IMP-1 for imipenem and meropenem are nearly identical; however, for IMP-6, the kcat/Km for meropenem is 7-fold that for imipenem. In clinical practice, this may result in an ineffective therapeutic regimen and, consequently, in treatment failure. Here, we report the crystal structures of IMP-6 and IMP-1 with the same space group and similar cell constants at resolutions of 1.70 and 1.94 A, respectively. The overall structures of IMP-6 and IMP-1 are similar. However, the loop region (residues 60-66), which participates in substrate binding, is more flexible in IMP-6 than in IMP-1. This difference in flexibility determines the substrate specificity of IMP-type metallo-beta-lactamases for imipenem and meropenem. The amino acid at position 262 alters the mobility of His263; this affects the flexibility of the loop via a hydrogen bond with Pro68, which plays the role of a hinge in IMP-type metallo-beta-lactamases. The substitution of Pro68 with a glycine elicited an increase in the Km of IMP-6 for imipenem, whereas the affinity for meropenem remained unchanged.

Structural insights into the substrate specificity of IMP-6 and IMP-1 metallo-beta-lactamases.,Yamamoto K, Tanaka H, Kurisu G, Nakano R, Yano H, Sakai H J Biochem. 2022 Dec 27;173(1):21-30. doi: 10.1093/jb/mvac080. PMID:36174533^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.