View source for 4em4


==Crystal Structure of Staphylococcus aureus bound with the covalent inhibitor Pethyl-VS-CoA==
<StructureSection load='4em4' size='340' side='right'caption='[[4em4]], [[Resolution|resolution]] 1.82&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4em4]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Staphylococcus_aureus_subsp._aureus_USA300 Staphylococcus aureus subsp. aureus USA300]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4EM4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4EM4 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.821&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA8:[[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-4-oxidanyl-3-phosphonooxy-oxolan-2-yl]methoxy-oxidanyl-phosphoryl]+[(3R)-2,2-dimethyl-3-oxidanyl-4-oxidanylidene-4-[[3-oxidanylidene-3-[4-(phenylsulfonyl)butylamino]propyl]amino]butyl]+hydrogen+phosphate'>CA8</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4em4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4em4 OCA], [https://pdbe.org/4em4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4em4 RCSB], [https://www.ebi.ac.uk/pdbsum/4em4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4em4 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/CDR_STAA3 CDR_STAA3] Catalyzes specifically the NADPH-dependent reduction of coenzyme A disulfide.[HAMAP-Rule:MF_01608]
<div style="background-color:#fffaf0;">
== 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<ref>PMID:22954034</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4em4" style="background-color:#fffaf0;"></div>

==See Also==
*[[Coenzyme A-Disulfide Reductase|Coenzyme A-Disulfide Reductase]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Staphylococcus aureus subsp. aureus USA300]]
[[Category: Claiborne A]]
[[Category: Edwards JS]]
[[Category: Redinbo MR]]
[[Category: Wallace BD]]