8SQ7

X-ray crystal structure of Acinetobacter baumanii beta-lactamase variant OXA-82 K83D in complex with doripenem

Summary for 8SQ7

• Entry DOI: 10.2210/pdb8sq7/pdb
• Descriptor: Beta-lactamase OXA-82, (4R,5S)-5-[(2S,3R)-3-hydroxy-1-oxobutan-2-yl]-4-methyl-3-({(3S,5S)-5-[(sulfamoylamino)methyl]pyrrolidin-3-yl}sulfanyl)-4,5-dihydro-1H-pyrrole-2-carboxylic acid, CITRATE ANION, ... (5 entities in total)
• Functional Keywords: acinetobacter beta-lactamase complex carbapenem doripenem, hydrolase, hydrolase-inhibitor, antibiotic complex, hydrolase/inhibitor, antibiotic
• Biological source: Acinetobacter baumannii
• Total number of polymer chains: 8
• Total formula weight: 229325.02

Authors

Powers, R.A.,Leonard, D.A.,June, C.M.,Szarecka, A.,Wawrzak, Z. (deposition date: 2023-05-04, release date: 2024-05-22, Last modification date: 2024-10-30)

Primary citation

Klamer, Z.L.,June, C.M.,Wawrzak, Z.,Taracila, M.A.,Grey, J.A.,Benn, A.M.I.,Russell, C.P.,Bonomo, R.A.,Powers, R.A.,Leonard, D.A.,Szarecka, A.
Structural and Dynamic Features of Acinetobacter baumannii OXA-66 beta-Lactamase Explain Its Stability and Evolution of Novel Variants.
J.Mol.Biol., 436:168603-168603, 2024

PubMed Abstract: OXA-66 is a member of the OXA-51 subfamily of class D β-lactamases native to the Acinetobacter genus that includes Acinetobacter baumannii, one of the ESKAPE pathogens and a major cause of drug-resistant nosocomial infections. Although both wild type OXA-66 and OXA-51 have low catalytic activity, they are ubiquitous in the Acinetobacter genomes. OXA-51 is also remarkably thermostable. In addition, newly emerging, single and double amino acid variants show increased activity against carbapenems, indicating that the OXA-51 subfamily is growing and gaining clinical significance. In this study, we used molecular dynamics simulations, X-ray crystallography, and thermal denaturation data to examine and compare the dynamics of OXA-66 wt and its gain-of-function variants: I129L (OXA-83), L167V (OXA-82), P130Q (OXA-109), P130A, and W222L (OXA-234). Our data indicate that OXA-66 wt also has a high melting temperature, and its remarkable stability is due to an extensive and rigid hydrophobic bridge formed by a number of residues around the active site and harbored by the three loops, P, Ω, and β5-β6. Compared to the WT enzyme, the mutants exhibit higher flexibility only in the loop regions, and are more stable than other robust carbapenemases, such as OXA-23 and OXA-24/40. All the mutants show increased rotational flexibility of residues I129 and W222, which allows carbapenems to bind. Overall, our data support the hypothesis that structural features in OXA-51 and OXA-66 promote evolution of multiple highly stable variants with increased clinical relevance in A. baumannii.

PubMed: 38729259
DOI: 10.1016/j.jmb.2024.168603

Experimental method

X-RAY DIFFRACTION (1.78 Å)