6p52

Crystal structure of transpeptidase domain of PBP2 from Neisseria gonorrhoeae with a bound phosphate at the active site

spinqualitylabelsall models 6p52, resolution 1.83Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6p52 is a 2 chain structure with sequence from Neisseria gonorrhoeae. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.83Å Ligands: PO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function PBP2_NEIGO Synthesis of cross-linked peptidoglycan from the lipid intermediates. Publication Abstract from PubMed Resistance of Neisseria gonorrhoeae to extended-spectrum cephalosporins (ESCs) has become a major threat to human health. The primary mechanism by which N. gonorrhoeae becomes resistant to ESCs is by acquiring a mosaic penA gene, encoding penicillin-binding protein 2 (PBP2) variants. Such variants contain up to 62 mutations compared with wild-type, of which a subset contribute to resistance. To interpret molecular mechanisms underpinning cephalosporin resistance, it is necessary to know how PBP2 is acylated by ESCs. Here, we report the crystal structures of the transpeptidase domain of wild-type PBP2 in complex with cefixime and ceftriaxone, along with structures of PBP2 in apo form and with a phosphate ion bound in the active site at resolutions of 1-7-1.9 A. These structures reveal that acylation of PBP2 by ESCs is accompanied by rotation of the Thr498 sidechain in the KTG motif to contact the cephalosporin carboxylate, twisting of the beta3 strand to form the oxyanion hole, and rolling of the beta3-beta4 loop toward the active site. Recognition of the cephalosporin carboxylate appears to be the key trigger for formation of an acylation-competent state of PBP2. The structures also begin to explain the impact of mutations implicated in ESC resistance. In particular, a G545S mutation may hinder twisting of beta3 because its sidechain hydroxyl forms a hydrogen bond with Thr498. Overall, our data suggest that acylation is initiated by conformational changes elicited or trapped by binding of ESCs and that these movements are restricted by mutations associated with resistance against ESCs. Recognition of the beta-lactam Carboxylate Triggers Acylation of Neisseria gonorrhoeae Penicillin-Binding Protein 2.,Singh A, Tomberg J, Nicholas RA, Davies C J Biol Chem. 2019 Jul 30. pii: RA119.009942. doi: 10.1074/jbc.RA119.009942. PMID:31362987 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Penicillin-binding protein 3D structures

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