5wi3

Structure of Acinetobacter baumannii carbapenemase OXA-239 K82D bound to cefotaximeStructure of Acinetobacter baumannii carbapenemase OXA-239 K82D bound to cefotaxime

Structural highlights 5wi3 is a 2 chain structure with sequence from Acinetobacter sp. enrichment culture clone 8407. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.81Å Ligands: Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function I6YCI1_9GAMM Publication Abstract from PubMed OXA-239 is a class D carbapenemase isolated from an Acinetobacter baumannii strain found in Mexico. This enzyme is a variant of OXA-23 with three amino acid substitutions in or near the active site. These substitutions cause OXA-239 to hydrolyze late-generation cephalosporins and the monobactam aztreonam with greater efficiency than OXA-23. OXA-239 activity against the carbapenems doripenem and imipenem is reduced approximately 3-fold and 20-fold respectively. Further analysis demonstrated that two of the substitutions (P225S and D222N) are largely responsible for the observed alteration of kinetic parameters, while the third (S109L) may serve to stabilize the protein. Structures of OXA-239 with cefotaxime, doripenem and imipenem bound as acyl-intermediates were determined. These structures reveal that OXA-239 has increased flexibility in a loop that contains P225S and D222N. When carbapenems are bound, the conformation of this loop is essentially identical to that observed previously for OXA-23, with a narrow active site that makes extensive contacts to the ligand. When cefotaxime is bound, the loop can adopt a different conformation that widens the active site to allow binding of that bulky drug. This alternate conformation is made possible by P225S and further stabilized by D222N. Taken together, these results suggest that the three substitutions were selected to expand the substrate specificity profile of OXA-23 to cephalosporins and monobactams. The loss of activity against imipenem, however, suggests that there may be limits to the plasticity of class D enzymes with regard to evolving active sites that can effectively bind multiple classes of beta-lactam drugs. Multiple substitutions lead to increased loop flexibility and expanded specificity in Acinetobacter baumannii carbapenemase OXA-239.,Harper TM, June CM, Taracila MA, Bonomo RA, Powers RA, Leonard DA Biochem J. 2017 Dec 11. pii: BCJ20170702. doi: 10.1042/BCJ20170702. PMID:29229762 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

spinqualitylabelsall models 5wi3, resolution 1.81Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image