6un1

Crystal structure of Pseudomonas aeruginosa PBP3 in complex with temocillin

spinqualitylabelsall models 6un1, resolution 2.26Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6un1 is a 1 chain structure with sequence from Pseudomonas aeruginosa. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.26Å Ligands: TJ7 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function FTSI_PSEAE Catalyzes cross-linking of the peptidoglycan cell wall at the division septum (By similarity). Binds penicillin (PubMed:20580675).[HAMAP-Rule:MF_02080] Publication Abstract from PubMed The prevalence of multi-drug resistant Pseudomonas aeruginosa has led to the re-examination of older 'forgotten' drugs, such as temocillin, for their ability to combat resistant microbes. Temocillin is the 6-alpha-methoxy analogue of ticarcillin, a carboxypenicillin with well characterized antipseudomonal properties. The alpha-methoxy modification confers resistance to serine beta-lactamases, yet temocillin is ineffective against P. aeruginosa growth. The origins of temocillin's inferior antibacterial properties against P. aeruginosa have remained relatively unexplored. Here we analyze the reaction kinetics, protein stability, and binding conformations of temocillin and ticarcillin with penicillin-binding protein 3 (PBP3), an essential PBP in P. aeruginosa We show the 6-alpha-methoxy group perturbs the stability of the PBP3 acyl-enzyme, which manifests in an elevated koff in biochemical assays comparing temocillin with ticarcillin. Complex crystal structures with PBP3 reveal similar binding modes of the two drugs, but with important differences. Most notably, the 6-alpha-methoxy group disrupts a high-quality hydrogen bond with a conserved residue important for ligand binding, while also being inserted into a crowded active site, possibly destabilizing the active site and enabling water molecule from bulk solvent to access and cleave the acyl-enzyme bond. This hypothesis is supported by the observation that the acyl-enzyme complex of temocillin has reduced thermal stability compared with ticarcillin. Furthermore, we explore temocillin's mechanism of beta-lactamase inhibition with a high-resolution complex structure of CTX-M-14 class A serine beta-lactamase. The results suggest the alpha-methoxy group prevents hydrolysis by locking the compound into an unexpected conformation that impedes access of the catalytic water to the acyl-enzyme adduct. Influence of the alpha-methoxy group on the reaction of temocillin with Pseudomonas aeruginosa PBP3 and CTX-M-14 beta-lactamase.,Sacco MD, Kroeck KG, Kemp MT, Zhang X, Andrews LD, Chen Y Antimicrob Agents Chemother. 2019 Nov 4. pii: AAC.01473-19. doi:, 10.1128/AAC.01473-19. PMID:31685462 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Penicillin-binding protein 3D structures

Proteopedia Page Contributors and Editors (what is this?)

OCA