5zft | pdb_00005zft

Crystal structure of beta-lactamase PenP mutant-E166Y in complex with cephaloridine as "pre-deacylation" intermediate

spinqualitylabelsall models 5zft, resolution 1.93Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5zft is a 2 chain structure with sequence from "clostridium_licheniforme"_weigmann_1898 "clostridium licheniforme" weigmann 1898. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: CED Gene: penP, blaP ("Clostridium licheniforme" Weigmann 1898) Activity: Beta-lactamase, with EC number 3.5.2.6 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Serine-based beta-lactamases of Class A, C and D all rely on a key water molecule to hydrolyze and inactivate beta-lactam antibiotics. This process involves two conserved catalytic steps. In the first acylation step, the beta-lactam antibiotic forms an acyl-enzyme intermediate (ES*) with the catalytic serine residue. In the second deacylation step, an activated water molecule serves as nucleophile (WAT_Nu) to attack ES* and release the inactivated beta-lactam. The coordination and activation of WAT_Nu is not fully understood. Using time-resolved x-ray crystallography and QM/MM simulations, we analyzed three intermediate structures of Class A beta-lactamase PenP as it slowly hydrolyzed cephaloridine. WAT_Nu is centrally located in the apo structure but becomes slightly displaced away by ES* in the post-acylation structure. In the deacylation structure, WAT_Nu moves back and is positioned along the Burgi-Dunitz trajectory with favorable energetic profile to attack ES*. Unexpectedly, WAT_Nu is also found to adopt a catalytically incompetent conformation in the deacylation structure forming a hydrogen bond with ES*. Our results reveal that ES* plays a significant role in coordinating and activating WAT_Nu through subtle yet distinct interactions at different stages of the catalytic process. These interactions may serve as potential targets to circumvent beta-lactamase-mediated antibiotic resistance. The hydrolytic water molecule of Class A beta-lactamase relies on the acyl-enzyme intermediate ES* for proper coordination and catalysis.,He Y, Lei J, Pan X, Huang X, Zhao Y Sci Rep. 2020 Jun 23;10(1):10205. doi: 10.1038/s41598-020-66431-w. PMID:32576842 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Beta-lactamase 3D structures

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