3MKE

SHV-1 beta-lactamase complex with LP06

3MKE の概要

• エントリーDOI: 10.2210/pdb3mke/pdb
• 関連するPDBエントリー: 3MKF
• 分子名称: Beta-lactamase SHV-1, CYCLOHEXYL-HEXYL-BETA-D-MALTOSIDE, PINACOL[[2-AMINO-ALPHA-(1-CARBOXY-1-METHYLETHOXYIMINO)-4-THIAZOLEACETYL]AMINO]METHANEBORONATE, ... (5 entities in total)
• 機能のキーワード: beta-lactamase, boronic acid transition state inhibitor, drug design, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Klebsiella pneumoniae
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 30666.61

構造登録者

van den Akker, F.,Ke, W. (登録日: 2010-04-14, 公開日: 2010-11-24, 最終更新日: 2024-11-06)

主引用文献

Ke, W.,Sampson, J.M.,Ori, C.,Prati, F.,Drawz, S.M.,Bethel, C.R.,Bonomo, R.A.,van den Akker, F.
Novel Insights into the Mode of Inhibition of Class A SHV-1 {beta}-Lactamases Revealed by Boronic Acid Transition State Inhibitors.
Antimicrob.Agents Chemother., 55:174-183, 2011

PubMed Abstract: Boronic acid transition state inhibitors (BATSIs) are potent class A and C β-lactamase inactivators and are of particular interest due to their reversible nature mimicking the transition state. Here, we present structural and kinetic data describing the inhibition of the SHV-1 β-lactamase, a clinically important enzyme found in Klebsiella pneumoniae, by BATSI compounds possessing the R1 side chains of ceftazidime and cefoperazone and designed variants of the latter, compounds 1 and 2. The ceftazidime and cefoperazone BATSI compounds inhibit the SHV-1 β-lactamase with micromolar affinity that is considerably weaker than their inhibition of other β-lactamases. The solved crystal structures of these two BATSIs in complex with SHV-1 reveal a possible reason for SHV-1's relative resistance to inhibition, as the BATSIs adopt a deacylation transition state conformation compared to the usual acylation transition state conformation when complexed to other β-lactamases. Active-site comparison suggests that these conformational differences might be attributed to a subtle shift of residue A237 in SHV-1. The ceftazidime BATSI structure revealed that the carboxyl-dimethyl moiety is positioned in SHV-1's carboxyl binding pocket. In contrast, the cefoperazone BATSI has its R1 group pointing away from the active site such that its phenol moiety moves residue Y105 from the active site via end-on stacking interactions. To work toward improving the affinity of the cefoperazone BATSI, we synthesized two variants in which either one or two extra carbons were added to the phenol linker. Both variants yielded improved affinity against SHV-1, possibly as a consequence of releasing the strain of its interaction with the unusual Y105 conformation.

PubMed: 21041505
DOI: 10.1128/AAC.00930-10

実験手法

X-RAY DIFFRACTION (1.75 Å)