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== Function == | == Function == | ||
[https://www.uniprot.org/uniprot/BLKPC_KLEPN BLKPC_KLEPN] Hydrolyzes carbapenems, penicillins, cephalosporins and monobactams with varying efficiency. | [https://www.uniprot.org/uniprot/BLKPC_KLEPN BLKPC_KLEPN] Hydrolyzes carbapenems, penicillins, cephalosporins and monobactams with varying efficiency. | ||
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== Publication Abstract from PubMed == | |||
Class A carbapenemases are a major threat to the potency of carbapenem antibiotics. A widespread carbapenemase, KPC-2, is not easily inhibited by beta-lactamase inhibitors (i.e., clavulanic acid, sulbactam, and tazobactam). To discover different mechanisms of inhibition of KPC-2, we determined the crystal structures of KPC-2 with two beta-lactamase inhibitors that possess different inactivation mechanisms and kinetics. The first complex is of a small boronic acid compound, 3-nitrophenyl boronic acid (3-NPBA) bound to KPC-2 determined at 1.62 A resolution. 3-NPBA demonstrates a K(m) value of 1.0 +/- 0.1 muM for KPC-2 and blocks the active site by making a reversible covalent interaction with the catalytic S70 residue. The two boron hydroxyl atoms of 3-NPBA are positioned in the oxyanion hole and the deacylation water pocket, respectively. In addition, the aromatic ring of 3-NPBA makes an edge-to-face interaction with W105 in the active site. The structure of KPC-2 with the penam sulfone, PSR-3-226, was determined at 1.26 A resolution. PSR-3-226 displays a K(m) value of 3.8 +/- 0.4 muM for KPC-2 and the k(inact) is 0.034 +/- 0.003 s(-1). Covalently bound to S70, PSR-3-226 forms a trans-enamine intermediate in the KPC-2 active site. The predominant active site interactions are generated via the carbonyl oxygen, which resides in the oxyanion hole, and the carboxyl moiety of PSR-3-226 which interacts with N132, N170, and E166. 3-NPBA and PSR-3-226 are the first beta-lactamase inhibitors to be trapped as an acyl-enzyme complex with KPC-2. The structural and inhibitory insights gained herein could aid in the design of potent KPC-2 inhibitors. | |||
Crystal Structures of KPC-2 beta-Lactamase in Complex with 3-NPBA and PSR-3-226.,Ke W, Bethel CR, Papp-Wallace KM, Pagadala SR, Nottingham M, Fernandez D, Buynak JD, Bonomo RA, van den Akker F Antimicrob Agents Chemother. 2012 Feb 13. PMID:22330909<ref>PMID:22330909</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
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==See Also== | ==See Also== | ||
*[[Beta-lactamase 3D structures|Beta-lactamase 3D structures]] | *[[Beta-lactamase 3D structures|Beta-lactamase 3D structures]] | ||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||