5xhr

Crystal structure of P99 beta-lactamase in complex with a penicillin derivative MPC-1

spinqualitylabelsall models 5xhr, resolution 1.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5xhr is a 1 chain structure with sequence from Enterobacter cloacae. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.8Å Ligands: PXH Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function AMPC_ENTCL This protein is a serine beta-lactamase with a substrate specificity for cephalosporins. Publication Abstract from PubMed Bacterial beta-lactamases readily inactivate most penicillins and cephalosporins by hydrolyzing and "opening" their signature beta-lactam ring. In contrast, carbapenems resist hydrolysis by many serine-based class A, C, and D beta-lactamases due to their unique stereochemical features. To improve the resistance profile of penicillins, we synthesized a modified penicillin molecule, MPC-1, by "grafting" carbapenem-like stereochemistry onto the penicillin core. Chemical modifications include the trans conformation of hydrogen atoms at C-5 and C-6 instead of cis, and a 6-alpha hydroxyethyl moiety to replace the original 6-beta aminoacyl group. MPC-1 selectively inhibits class C beta-lactamases, such as P99, by forming a nonhydrolyzable acyl adduct, and its inhibitory potency is approximately 2 to 5 times higher than that for clinically used beta-lactamase inhibitors clavulanate and sulbactam. The crystal structure of MPC-1 forming the acyl adduct with P99 reveals a novel binding mode for MPC-1 that resembles carbapenem bound in the active site of class A beta-lactamases. Furthermore, in this novel binding mode, the carboxyl group of MPC-1 blocks the deacylation reaction by occluding the critical catalytic water molecule and renders the acyl adduct nonhydrolyzable. Our results suggest that by incorporating carbapenem-like stereochemistry, the current collection of over 100 penicillins and cephalosporins can be modified into candidate compounds for development of novel beta-lactamase inhibitors. Modified Penicillin Molecule with Carbapenem-Like Stereochemistry Specifically Inhibits Class C beta-Lactamases.,Pan X, He Y, Chen T, Chan KF, Zhao Y Antimicrob Agents Chemother. 2017 Nov 22;61(12). pii: AAC.01288-17. doi:, 10.1128/AAC.01288-17. Print 2017 Dec. PMID:28971874 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Beta-lactamase 3D structures

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