Structural insights into the substrate specificity of IMP-6 and IMP-1 metallo-β-lactamases

Author:

Yamamoto Keizo1,Tanaka Hideaki2,Kurisu Genji2,Nakano Ryuichi3,Yano Hisakazu3,Sakai Hiromi1

Affiliation:

1. Nara Medical University Department of Chemistry, , 840 Shojo-Cho, Kashihara, Nara 634-8521, Japan

2. Osaka University Institute for Protein Research, , 3-2 Yamadaoka, Suita, Osaka 565-0871, Japan

3. Nara Medical University Department of Microbiology and Infectious Diseases, , 840 Shojo-Cho, Kashihara, Nara 634-8521, Japan

Abstract

Abstract IMP-type metallo-β-lactamases confer resistance to carbapenems and a broad spectrum of β-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 Å, 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-β-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-β-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.

Funder

Japan Society for the Promotion of Sciences

Grants-in-Aid for Scientific Research

Publisher

Oxford University Press (OUP)

Subject

Molecular Biology,Biochemistry,General Medicine

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