6xqv

Crystal structure of the catalytic domain of PBP2 S310A from Neisseria gonorrhoeae in a pre-acylation complex with ceftriaxone

spinqualitylabelsall models 6xqv, resolution 2.05Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6xqv 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 2.05Å Ligands: 9F2, CL, SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function PBP2_NEIGO Synthesis of cross-linked peptidoglycan from the lipid intermediates. Publication Abstract from PubMed Resistance to the extended-spectrum cephalosporin ceftriaxone in the pathogenic bacteria Neisseria gonorrhoeae is conferred by mutations in penicillin-binding protein 2 (PBP2), the lethal target of the antibiotic, but how these mutations exert their effect at the molecular level is unclear. Using solution NMR, X-ray crystallography, and isothermal titration calorimetry, we report that WT PBP2 exchanges dynamically between a low-affinity state with an extended beta3-beta4 loop conformation and a high-affinity state with an inward beta3-beta4 loop conformation. Histidine-514, which is located at the boundary of the beta4 strand, plays an important role during the exchange between these two conformational states. We also find that mutations present in PBP2 from H041, a ceftriaxone-resistant strain of N. gonorrhoeae, increase resistance to ceftriaxone by destabilizing the inward beta3-beta4 loop conformation or stabilizing the extended beta3-beta4 loop conformation to favor the low-affinity drug-binding state. These observations reveal a unique mechanism for ceftriaxone resistance, whereby mutations in PBP2 lower the proportion of target molecules in the high-affinity drug-binding state and thus reduce inhibition at lower drug concentrations. Mutations in PBP2 from ceftriaxone-resistant Neisseria gonorrhoeae alter the dynamics of the beta3-beta4 loop to favor a low-affinity drug-binding state.,Fenton BA, Tomberg J, Sciandra CA, Nicholas RA, Davies C, Zhou P J Biol Chem. 2021 Oct;297(4):101188. doi: 10.1016/j.jbc.2021.101188. Epub 2021, Sep 13. PMID:34529975 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Penicillin-binding protein 3D structures

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