5x5g

Crystal structure of TLA-3 extended-spectrum beta-lactamase in a complex with OP0595

spinqualitylabelsall models 5x5g, resolution 2.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5x5g is a 1 chain structure with sequence from Serratia marcescens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2Å Ligands: NA, OP0, SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function A0A0B6VPP7_SERMA Publication Abstract from PubMed The development of effective inhibitors that block extended-spectrum beta-lactamases (ESBLs) and restore the action of beta-lactams represents an effective strategy against ESBL-producing Enterobacteriaceae We evaluated the inhibitory effects of the diazabicyclooctanes avibactam and OP0595 against TLA-3, an ESBL that we identified previously. Avibactam and OP0595 inhibited TLA-3 with apparent inhibitor constants (Kiapp) of 1.71 +/- 0.10 and 1.49 +/- 0.05 muM, respectively, and could restore susceptibility to cephalosporins in the TLA-3-producing Escherichia coli strain. The value of the second-order acylation rate constant (k2/K, where k2 is the acylation rate constant and K is the equilibrium constant) of avibactam [(3.25 +/- 0.03) x 10(3) M(-1) . s(-1)] was closer to that of class C and D beta-lactamases (k2/K, <10(4) M(-1) . s(-1)) than that of class A beta-lactamases (k2/K, >10(4) M(-1) . s(-1)). In addition, we determined the structure of TLA-3 and that of TLA-3 complexed with avibactam or OP0595 at resolutions of 1.6, 1.6, and 2.0 A, respectively. TLA-3 contains an inverted Omega loop and an extended loop between the beta5 and beta6 strands (insertion after Ser237), which appear only in PER-type class A beta-lactamases. These structures might favor the accommodation of cephalosporins harboring bulky R1 side chains. TLA-3 presented a high catalytic efficiency (kcat/Km ) against cephalosporins, including cephalothin, cefuroxime, and cefotaxime. Avibactam and OP0595 bound covalently to TLA-3 via the Ser70 residue and made contacts with residues Ser130, Thr235, and Ser237, which are conserved in ESBLs. Additionally, the sulfate group of the inhibitors formed polar contacts with amino acid residues in a positively charged pocket of TLA-3. Our findings provide a structural template for designing improved diazabicyclooctane-based inhibitors that are effective against ESBL-producing Enterobacteriaceae. Structural Insights into the TLA-3 Extended-Spectrum beta-Lactamase and Its Inhibition by Avibactam and OP0595.,Jin W, Wachino JI, Yamaguchi Y, Kimura K, Kumar A, Yamada M, Morinaka A, Sakamaki Y, Yonezawa M, Kurosaki H, Arakawa Y Antimicrob Agents Chemother. 2017 Sep 22;61(10). pii: AAC.00501-17. doi:, 10.1128/AAC.00501-17. Print 2017 Oct. PMID:28739781 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Beta-lactamase 3D structures

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