The structure of a doripenem-bound OXA-51 class D [beta]-lactamase variant with enhanced carbapenemase activity

OXA-51 is a class D [beta]-lactamase that is thought to be the native carbapenemase of Acinetobacter baumannii. Many variants of OXA-51 containing active site substitutions have been identified from A. baumannii isolates, and some of these substitutions increase hydrolytic activity toward carbapenem...

Full description

Saved in:
Bibliographic Details
Published in:Protein science 2016-12, Vol.25 (12), p.2152
Main Authors: June, Cynthia M, Muckenthaler, Taylor J, Schroder, Emma C, Klamer, Zachary L, Wawrzak, Zdzislaw, Powers, Rachel A, Szarecka, Agnieszka, Leonard, David A
Format: Article
Language:English
Subjects:
Affinity
Antibiotics
Binding
Binding sites
Carbapenemase
Carbapenems
Chain mobility
Chains
Crystal structure
High resolution
Indoles
Isoleucine
Leucine
Ligands
Meropenem
Molecular dynamics
Molecular structure
Orientation
Simulation
Substrates
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:OXA-51 is a class D [beta]-lactamase that is thought to be the native carbapenemase of Acinetobacter baumannii. Many variants of OXA-51 containing active site substitutions have been identified from A. baumannii isolates, and some of these substitutions increase hydrolytic activity toward carbapenem antibiotics. We have determined the high-resolution structures of apo OXA-51 and OXA-51 with one such substitution (I129L) with the carbapenem doripenem trapped in the active site as an acyl-intermediate. The structure shows that acyl-doripenem adopts an orientation very similar to carbapenem ligands observed in the active site of OXA-24/40 (doripenem) and OXA-23 (meropenem). In the OXA-51 variant/doripenem complex, the indole ring of W222 is oriented away from the doripenem binding site, thereby eliminating a clash that is predicted to occur in wildtype OXA-51. Similarly, in the OXA-51 variant complex, L129 adopts a different rotamer compared to I129 in wildtype OXA-51. This alternative position moves its side chain away from the hydroxyethyl moiety of doripenem and relieves another potential clash between the enzyme and carbapenem substrates. Molecular dynamics simulations of OXA-51 and OXA-51 I129L demonstrate that compared to isoleucine, a leucine at this position greatly favors a rotamer that accommodates the ligand. These results provide a molecular justification for how this substitution generates enhanced binding affinity for carbapenems, and therefore helps explain the prevalence of this substitution in clinical OXA-51 variants. PDB Code(s): 5KZH; 5L2F
ISSN:0961-8368
1469-896X
DOI:10.1002/pro.3040