6PXX

Class D beta-lactamase in complex with beta-lactam antibiotic

Summary for 6PXX

• Entry DOI: 10.2210/pdb6pxx/pdb
• Descriptor: Beta-lactamase, (2~{S},3~{R})-3-methyl-2-[(2~{S},3~{R})-3-oxidanyl-1-oxidanylidene-butan-2-yl]-4-[(3~{S},5~{S})-5-[(sulfamoylamino)meth yl]pyrrolidin-3-yl]sulfanyl-3,4-dihydro-2~{H}-pyrrole-5-carboxylic acid, 1,2-ETHANEDIOL, ... (6 entities in total)
• Functional Keywords: inhibitor, lactamase, hydrolase, hydrolase-antibiotic-inhibitor complex, hydrolase/antibiotic/inhibitor
• Biological source: Klebsiella pneumoniae
• Total number of polymer chains: 2
• Total formula weight: 62141.84

Authors

van den Akker, F.,Kumar, V. (deposition date: 2019-07-28, release date: 2019-10-09, Last modification date: 2024-11-20)

Primary citation

Papp-Wallace, K.M.,Kumar, V.,Zeiser, E.T.,Becka, S.A.,van den Akker, F.
Structural Analysis of The OXA-48 Carbapenemase Bound to A "Poor" Carbapenem Substrate, Doripenem.
Antibiotics, 8:-, 2019

PubMed Abstract: Carbapenem-resistant Enterobacteriaceae are a significant threat to public health, and a major resistance determinant that promotes this phenotype is the production of the OXA-48 carbapenemase. The activity of OXA-48 towards carbapenems is a puzzling phenotype as its hydrolytic activity against doripenem is non-detectable. To probe the mechanistic basis for this observation, we determined the 1.5 Å resolution crystal structure of the deacylation deficient K73A variant of OXA-48 in complex with doripenem. Doripenem is observed in the ΔR and ΔS tautomeric states covalently attached to the catalytic S70 residue. Likely due to positioning of residue Y211, the carboxylate moiety of doripenem is making fewer hydrogen bonding/salt-bridge interactions with R250 compared to previously determined carbapenem OXA structures. Moreover, the hydroxyethyl side chain of doripenem is making van der Waals interactions with a key V120 residue, which likely affects the deacylation rate of doripenem. We hypothesize that positions V120 and Y211 play important roles in the carbapenemase profile of OXA-48. Herein, we provide insights for the further development of the carbapenem class of antibiotics that could render them less effective to hydrolysis by or even inhibit OXA carbapenemases.

PubMed: 31514291
DOI: 10.3390/antibiotics8030145

Experimental method

X-RAY DIFFRACTION (1.5 Å)