6p98

OXA-48 carbapanemase, meropenem complex

spinqualitylabelsall models 6p98, resolution 1.75Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6p98 is a 2 chain structure with sequence from Klebsiella pneumoniae. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.75Å Ligands: CA, CD, CL, KE1 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function Q6XEC0_KLEPN Publication Abstract from PubMed Carbapenem-hydrolyzing class D carbapenemases (CHDLs) are enzymes that produce resistance to the last resort carbapenem antibiotics, severely compromising available therapeutic options for treatment of life-threatening infections. A broad variety of CHDLs, including OXA-23, OXA-24/40 and OXA-58, circulate in Acinetobacter baumannii, while the OXA-48 CHDL is predominant in Enterobacteriaceae Extensive structural studies of A. baumannii enzymes provided important information regarding their interactions with carbapenems and significantly contributed to the understanding of the mechanism of their carbapenemase activity. However, the interactions between carbapenems and OXA-48 have not yet been elucidated. We determined X-ray crystal structures of the acyl-enzyme complexes of OXA-48 with four carbapenems, imipenem, meropenem, ertapenem and doripenem, and compared them with known carbapenem complexes of A. baumannii CHDLs. In the A. baumannii enzymes, acylation by carbapenems triggers significant displacement of one of two conserved hydrophobic surface residues, resulting in formation of a channel for entry of the deacylating water into the active site. We show that such channel pre-exists in apo-OXA-48 and only minor displacement of the conserved hydrophobic surface residues occurs upon formation of OXA-48 acyl-enzyme intermediates. We also demonstrate that extensive hydrophobic interactions that occur between a conserved hydrophobic bridge of the A. baumannii CHDLs and the carbapenem tails, are lost in OXA-48 in the absence of an equivalent bridge structure. These data highlight significant differences between the interactions of carbapenems with OXA-48 when compared to those with A. baumannii enzymes and provide important insights into the mechanism of carbapenemase activity of the major Enterobacteriaceae CHDL, OXA-48. Structural Insights into the Mechanism of Carbapenemase Activity of the OXA-48 beta-Lactamase.,Smith CA, Stewart NK, Toth M, Vakulenko SB Antimicrob Agents Chemother. 2019 Jul 29. pii: AAC.01202-19. doi:, 10.1128/AAC.01202-19. PMID:31358584 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Beta-lactamase 3D structures

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