4eqs

Crystal structure of the Y419F mutant of Staphylococcus aureus CoADR

spinqualitylabelsall models 4eqs, resolution 1.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4eqs is a 2 chain structure with sequence from Staphylococcus aureus subsp. aureus USA300. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.5Å Ligands: CL, COA, FAD, MG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function CDR_STAA3 Catalyzes specifically the NADPH-dependent reduction of coenzyme A disulfide.[HAMAP-Rule:MF_01608] Publication Abstract from PubMed Disruption of the unusual thiol-based redox homeostasis mechanisms in Staphylococcus aureus represents a unique opportunity to identify new metabolic processes and new targets for intervention. Targeting uncommon aspects of CoASH biosynthetic and redox functions in S. aureus, the antibiotic CJ-15,801 has recently been demonstrated to be an antimetabolite of the CoASH biosynthetic pathway in this organism; CoAS-mimetics containing alpha,beta-unsaturated sulfone and carboxyl moieties have also been exploited as irreversible inhibitors of S. aureus coenzyme A-disulfide reductase (SaCoADR). In this work we have determined the crystal structures of three of these covalent SaCoADR-inhibitor complexes, prepared by inactivation of wild-type enzyme during turnover. The structures reveal the covalent linkage between the active-site Cys43-S(gamma) and C(beta) of the vinyl sulfone or carboxyl moiety. The full occupancy of two inhibitor molecules per enzyme dimer, together with kinetic analyses of the wild-type/C43S heterodimer, indicates that half-sites-reactivity is not a factor during normal catalytic turnover. Further, we provide the structures of SaCoADR active-site mutants; in particular, Tyr419'-OH plays dramatic roles in directing intramolecular reduction of the Cys43-SSCoA redox center, in the redox asymmetry observed for the two FAD per dimer in NADPH titrations, and in catalysis. The two conformations observed for the Ser43 side chain in the C43S mutant structure lend support to a conformational switch for Cys43-S(gamma) during its catalytic Cys43-SSCoA/Cys43-SH redox cycle. Finally, the structures of the three inhibitor complexes provide a framework for design of more effective inhibitors with therapeutic potential against several major bacterial pathogens. Turnover-Dependent Covalent Inactivation of Staphylococcus aureus Coenzyme A-Disulfide Reductase by Coenzyme A-Mimetics: Mechanistic and Structural Insights.,Wallace BD, Edwards JS, Wallen JR, Moolman WJ, van der Westhuyzen R, Strauss E, Redinbo MR, Claiborne A Biochemistry. 2012 Oct 2;51(39):7699-711. doi: 10.1021/bi301026c. Epub 2012 Sep, 19. PMID:22954034 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Coenzyme A-Disulfide Reductase

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