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3v4x

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==The Biochemical and Structural Basis for Inhibition of Enterococcus faecalis HMG-CoA Synthase, mvaS, by Hymeglusin==
==The Biochemical and Structural Basis for Inhibition of Enterococcus faecalis HMG-CoA Synthase, mvaS, by Hymeglusin==
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<StructureSection load='3v4x' size='340' side='right' caption='[[3v4x]], [[Resolution|resolution]] 1.95&Aring;' scene=''>
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<StructureSection load='3v4x' size='340' side='right'caption='[[3v4x]], [[Resolution|resolution]] 1.95&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[3v4x]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/"enterococcus_proteiformis"_thiercelin_and_jouhaud_1903 "enterococcus proteiformis" thiercelin and jouhaud 1903]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3V4X OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3V4X FirstGlance]. <br>
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<table><tr><td colspan='2'>[[3v4x]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Enterococcus_faecalis Enterococcus faecalis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3V4X OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3V4X FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=F24:(7R,12R,13R)-13-FORMYL-12,14-DIHYDROXY-3,5,7-TRIMETHYLTETRADECA-2,4-DIENOIC+ACID'>F24</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.952&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3v4n|3v4n]]</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=F24:(7R,12R,13R)-13-FORMYL-12,14-DIHYDROXY-3,5,7-TRIMETHYLTETRADECA-2,4-DIENOIC+ACID'>F24</scene></td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">mvaS ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1351 "Enterococcus proteiformis" Thiercelin and Jouhaud 1903])</td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3v4x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3v4x OCA], [https://pdbe.org/3v4x PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3v4x RCSB], [https://www.ebi.ac.uk/pdbsum/3v4x PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3v4x ProSAT]</span></td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Hydroxymethylglutaryl-CoA_synthase Hydroxymethylglutaryl-CoA synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.3.10 2.3.3.10] </span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3v4x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3v4x OCA], [http://pdbe.org/3v4x PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3v4x RCSB], [http://www.ebi.ac.uk/pdbsum/3v4x PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3v4x ProSAT]</span></td></tr>
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</table>
</table>
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<div style="background-color:#fffaf0;">
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== Function ==
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== Publication Abstract from PubMed ==
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[https://www.uniprot.org/uniprot/HMGCS_ENTFL HMGCS_ENTFL] Catalyzes the condensation of acetyl-CoA with acetoacetyl-CoA to form 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). Functions in the mevalonate (MVA) pathway leading to isopentenyl diphosphate (IPP), a key precursor for the biosynthesis of isoprenoid compounds.<ref>PMID:12107122</ref> <ref>PMID:23794621</ref>
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Hymeglusin (1233A, F244, L-659-699) is established as a specific beta-lactone inhibitor of eukaryotic hydroxymethylglutaryl-CoA synthase (HMGCS). Inhibition results from formation of a thioester adduct to the active site cysteine. In contrast, the effects of hymeglusin on bacterial HMG-CoA synthase, mvaS, have been minimally characterized. Hymeglusin blocks growth of Enterococcus faecalis. After removal of the inhibitor from culture media, a growth curve inflection point at 3.1 h is observed (vs 0.7 h for the uninhibited control). Upon hymeglusin inactivation of purified E. faecalis mvaS, the thioester adduct is more stable than that measured for human HMGCS. Hydroxylamine cleaves the thioester adduct; substantial enzyme activity is restored at a rate that is 8-fold faster for human HMGCS than for mvaS. Structural results explain these differences in enzyme-inhibitor thioester adduct stability and solvent accessibility. The E. faecalis mvaS-hymeglusin cocrystal structure (1.95 A) reveals virtually complete occlusion of the bound inhibitor in a narrow tunnel that is largely sequestered from bulk solvent. In contrast, eukaryotic (Brassica juncea) HMGCS binds hymeglusin in a more solvent-exposed cavity.
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Biochemical and structural basis for inhibition of Enterococcus faecalis hydroxymethylglutaryl-CoA synthase, mvaS, by hymeglusin.,Skaff DA, Ramyar KX, McWhorter WJ, Barta ML, Geisbrecht BV, Miziorko HM Biochemistry. 2012 Jun 12;51(23):4713-22. doi: 10.1021/bi300037k. Epub 2012 May, 25. PMID:22510038<ref>PMID:22510038</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 3v4x" style="background-color:#fffaf0;"></div>
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== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Enterococcus proteiformis thiercelin and jouhaud 1903]]
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[[Category: Enterococcus faecalis]]
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[[Category: Hydroxymethylglutaryl-CoA synthase]]
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[[Category: Large Structures]]
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[[Category: Geisbrecht, B V]]
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[[Category: Geisbrecht BV]]
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[[Category: McWhorter, W J]]
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[[Category: McWhorter WJ]]
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[[Category: Miziorko, H M]]
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[[Category: Miziorko HM]]
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[[Category: Ramyar, K X]]
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[[Category: Ramyar KX]]
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[[Category: Skaff, D A]]
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[[Category: Skaff DA]]
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[[Category: Hydroxymethylglutaryl-coa synthase]]
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[[Category: Hymeglusin covalent adduct]]
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[[Category: Transferase-inhibitor complex]]
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Current revision

The Biochemical and Structural Basis for Inhibition of Enterococcus faecalis HMG-CoA Synthase, mvaS, by Hymeglusin

PDB ID 3v4x

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