3PAE

Crystal structure of the K84D mutant of OXA-24/40 in complex with doripenem

Summary for 3PAE

• Entry DOI: 10.2210/pdb3pae/pdb
• Related: 3ISG 3PAG
• Descriptor: Beta-lactamase, (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, SULFATE ION, ... (4 entities in total)
• Functional Keywords: hydrolase, carbapenemase, hydrolase-antibiotic complex, hydrolase/antibiotic
• Biological source: Acinetobacter baumannii
• Total number of polymer chains: 2
• Total formula weight: 56454.75

Authors

Powers, R.A.,Leonard, D.A.,Schneider, K.D. (deposition date: 2010-10-19, release date: 2011-01-19, Last modification date: 2023-09-06)

Primary citation

Schneider, K.D.,Ortega, C.J.,Renck, N.A.,Bonomo, R.A.,Powers, R.A.,Leonard, D.A.
Structures of the Class D Carbapenemase OXA-24 from Acinetobacter baumannii in Complex with Doripenem.
J.Mol.Biol., 406:583-594, 2011

PubMed Abstract: The emergence of class D β-lactamases with carbapenemase activity presents an enormous challenge to health practitioners, particularly with regard to the treatment of infections caused by Gram-negative pathogens such as Acinetobacter baumannii. Unfortunately, class D β-lactamases with carbapenemase activity are resistant to β-lactamase inhibitors. To better understand the details of the how these enzymes bind and hydrolyze carbapenems, we have determined the structures of two deacylation-deficient variants (K84D and V130D) of the class D carbapenemase OXA-24 with doripenem bound as a covalent acyl-enzyme intermediate. Doripenem adopts essentially the same configuration in both OXA-24 variant structures, but varies significantly when compared to the non-carbapenemase class D member OXA-1/doripenem complex. The alcohol of the 6α hydroxyethyl moiety is directed away from the general base carboxy-K84, with implications for activation of the deacylating water. The tunnel formed by the Y112/M223 bridge in the apo form of OXA-24 is largely unchanged by the binding of doripenem. The presence of this bridge, however, causes the distal pyrrolidine/sulfonamide group to bind in a drastically different conformation compared to doripenem bound to OXA-1. The resulting difference in the position of the side-chain bridge sulfur of doripenem is consistent with the hypothesis that the tautomeric state of the pyrroline ring contributes to the different carbapenem hydrolysis rates of OXA-1 and OXA-24. These findings represent a snapshot of a key step in the catalytic mechanism of an important class D enzyme, and might be useful for the design of novel inhibitors.

PubMed: 21215758
DOI: 10.1016/j.jmb.2010.12.042

Experimental method

X-RAY DIFFRACTION (2.1 Å)