3mkf

SHV-1 beta-lactamase complex with GB0301

spinqualitylabelsall models 3mkf, resolution 1.33Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3mkf is a 1 chain structure with sequence from "bacillus_pneumoniae"_(schroeter_1886)_flugge_1886 "bacillus pneumoniae" (schroeter 1886) flugge 1886. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: CZ7, MA4 Related: 3mke Gene: bla, shv1 ("Bacillus pneumoniae" (Schroeter 1886) Flugge 1886) Activity: Beta-lactamase, with EC number 3.5.2.6 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Boronic acid transition state inhibitors (BATSIs) are potent class A and C beta-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 SHV-1 beta-lactamase, a clinically important enzyme found in Klebsiella pneumoniae, by BATSI compounds possessing the R1 side chains of ceftazidime, cefoperazone, and designed variants of the latter. The ceftazidime and cefoperazone BATSI compounds inhibit SHV-1 beta-lactamase with micro-molar affinity which is considerably weaker compared to their inhibition of other beta-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 usual acylation transition state conformation when complexed to other beta-lactamases. Active site comparison suggests that these structural 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 towards 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. Novel insights into the mode of inhibition of class A SHV-1 {beta}-lactamase revealed by boronic acid transition state inhibitors.,Ke W, Sampson JM, Ori C, Prati F, Drawz SM, Bethel CR, Bonomo RA, van den Akker F Antimicrob Agents Chemother. 2010 Nov 1. PMID:21041505 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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