5KZH

High Resolution Structure of Acinetobacter baumannii beta-lactamase OXA-51

Summary for 5KZH

• Entry DOI: 10.2210/pdb5kzh/pdb
• Descriptor: Beta-lactamase, FORMIC ACID, ACETATE ION, ... (4 entities in total)
• Functional Keywords: hydrolase, antibiotic
• Biological source: Acinetobacter baumannii
• Total number of polymer chains: 4
• Total formula weight: 113281.60

Authors

June, C.M.,Powers, R.A.,Leonard, D.A. (deposition date: 2016-07-25, release date: 2016-08-17, Last modification date: 2025-04-02)

Primary citation

June, C.M.,Muckenthaler, T.J.,Schroder, E.C.,Klamer, Z.L.,Wawrzak, Z.,Powers, R.A.,Szarecka, A.,Leonard, D.A.
The structure of a doripenem-bound OXA-51 class D beta-lactamase variant with enhanced carbapenemase activity.
Protein Sci., 25:2152-2163, 2016

PubMed Abstract: OXA-51 is a class D β-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.

PubMed: 27636561
DOI: 10.1002/pro.3040

Experimental method

X-RAY DIFFRACTION (1.61 Å)