1ysl: Difference between revisions

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~~[[Image:1ysl.gif|left|200px]]<br /><applet load="1ysl" size="450" color="white" frame="true" align="right" spinBox="true"~~

~~caption="1ysl, resolution 1.90Å" />~~

~~'''Crystal structure of HMG-CoA synthase from Enterococcus faecalis with AcetoAcetyl-CoA ligand.'''<br />~~

==~~Overview~~==

==Crystal structure of HMG-CoA synthase from Enterococcus faecalis with AcetoAcetyl-CoA ligand.==

Biosynthesis of the isoprenoid precursor, isopentenyl diphosphate, is a, critical function in all independently living organisms. There are two, major pathways for this synthesis, the non-mevalonate pathway found in, most eubacteria and the mevalonate pathway found in animal cells and a, number of pathogenic bacteria. An early step in this pathway is the, condensation of acetyl-CoA and acetoacetyl-CoA into HMG-CoA, catalyzed by, the enzyme HMG-CoA synthase. To explore the possibility of a small, molecule inhibitor of the enzyme functioning as a non-cell wall, antibiotic, the structure of HMG-CoA synthase from Enterococcus faecalis, (MVAS) was determined by selenomethionine MAD phasing to 2.4 A and the, enzyme complexed with its second substrate, acetoacetyl-CoA, to 1.9 A., These structures show that HMG-CoA synthase from Enterococcus is a member, of the family of thiolase fold enzymes and, while similar to the recently, published HMG-CoA synthase structures from Staphylococcus aureus, exhibit, significant differences in the structure of the C-terminal domain. The, acetoacetyl-CoA binary structure demonstrates reduced coenzyme A and, acetoacetate covalently bound to the active site cysteine through a, thioester bond. This is consistent with the kinetics of the reaction that, have shown acetoacetyl-CoA to be a potent inhibitor of the overall, reaction, and provides a starting point in the search for a small molecule, inhibitor.

== Structural highlights ==

<table><tr><td colspan='2'>[[1ysl]] is a 2 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=1YSL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1YSL 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]] 1.9Å</td></tr>

<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AAE:ACETOACETIC+ACID'>AAE</scene>, <scene name='pdbligand=COA:COENZYME+A'>COA</scene>, <scene name='pdbligand=CSD:3-SULFINOALANINE'>CSD</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=1ysl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1ysl OCA], [https://pdbe.org/1ysl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1ysl RCSB], [https://www.ebi.ac.uk/pdbsum/1ysl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1ysl ProSAT]</span></td></tr>

</table>

== Function ==

[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>

== Evolutionary Conservation ==

[[Image:Consurf_key_small.gif|200px|right]]

Check<jmol>

<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ys/1ysl_consurf.spt"</scriptWhenChecked>

<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>

<text>to colour the structure by Evolutionary Conservation</text>

</jmolCheckbox>

</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1ysl ConSurf].

== Publication Abstract from PubMed ==

Biosynthesis of the isoprenoid precursor, isopentenyl diphosphate, is a critical function in all independently living organisms. There are two major pathways for this synthesis, the non-mevalonate pathway found in most eubacteria and the mevalonate pathway found in animal cells and a number of pathogenic bacteria. An early step in this pathway is the condensation of acetyl-CoA and acetoacetyl-CoA into HMG-CoA, catalyzed by the enzyme HMG-CoA synthase. To explore the possibility of a small molecule inhibitor of the enzyme functioning as a non-cell wall antibiotic, the structure of HMG-CoA synthase from Enterococcus faecalis (MVAS) was determined by selenomethionine MAD phasing to 2.4 A and the enzyme complexed with its second substrate, acetoacetyl-CoA, to 1.9 A. These structures show that HMG-CoA synthase from Enterococcus is a member of the family of thiolase fold enzymes and, while similar to the recently published HMG-CoA synthase structures from Staphylococcus aureus, exhibit significant differences in the structure of the C-terminal domain. The acetoacetyl-CoA binary structure demonstrates reduced coenzyme A and acetoacetate covalently bound to the active site cysteine through a thioester bond. This is consistent with the kinetics of the reaction that have shown acetoacetyl-CoA to be a potent inhibitor of the overall reaction, and provides a starting point in the search for a small molecule inhibitor.

~~==About this Structure==~~

X-ray crystal structures of HMG-CoA synthase from Enterococcus faecalis and a complex with its second substrate/inhibitor acetoacetyl-CoA.,Steussy CN, Vartia AA, Burgner JW 2nd, Sutherlin A, Rodwell VW, Stauffacher CV Biochemistry. 2005 Nov 1;44(43):14256-67. PMID:16245942<ref>PMID:16245942</ref>

~~1YSL is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure~~ of ~~sequence~~ from ~~[http://en.wikipedia.org/wiki/Enterococcus_faecalis~~ Enterococcus faecalis] with ~~SO4, COA, AAE and GOL as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Full crystallographic information is available from [http~~:/~~/ispc.weizmann.ac.il/oca-bin/ocashort?id=1YSL OCA].~~

~~==Reference==~~

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>

~~X-ray crystal structures of HMG-CoA synthase from Enterococcus faecalis and a complex with its second substrate~~/~~inhibitor acetoacetyl~~-~~CoA., Steussy CN, Vartia AA, Burgner JW 2nd, Sutherlin A, Rodwell VW, Stauffacher CV, Biochemistry. 2005 Nov 1;44(43):14256~~-~~67. PMID:[http~~://~~ispc.weizmann.ac.il/~~/~~pmbin/getpm?pmid=16245942 16245942]~~

</div>

== References ==

__TOC__

</StructureSection>

[[Category: Enterococcus faecalis]]

[[Category: ~~Hydroxymethylglutaryl-CoA synthase]]~~

[[Category: Large Structures]]

~~[[Category: Single protein~~]]

[[Category: Burgner II JW]]

[[Category: II~~, J.W.Burgner.~~]]

[[Category: Rodwell VW]]

[[Category: Rodwell~~, V.W.~~]]

[[Category: Stauffacher CV]]

[[Category: Stauffacher~~, C.V.~~]]

[[Category: Steussy CN]]

[[Category: Steussy~~, C.N.~~]]

[[Category: Sutherlin A]]

[[Category: Sutherlin, A.]]

[[Category: Vartia AA]]

[[Category: Vartia~~, A.A.]]~~

~~[[Category: AAE]]~~

~~[[Category: COA]]~~

~~[[Category: GOL]]~~

~~[[Category: SO4]]~~

~~[[Category: coenzymea]]~~

~~[[Category: thiolase family~~]]

~~''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Sun Nov 25 04:33:14 2007''~~

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@@ Line 1: / Line 1: @@
-[[Image:1ysl.gif|left|200px]]<br /><applet load="1ysl" size="450" color="white" frame="true" align="right" spinBox="true"
-caption="1ysl, resolution 1.90&Aring;" />
-'''Crystal structure of HMG-CoA synthase from Enterococcus faecalis with AcetoAcetyl-CoA ligand.'''<br />
-==Overview==
+==Crystal structure of HMG-CoA synthase from Enterococcus faecalis with AcetoAcetyl-CoA ligand.==
-Biosynthesis of the isoprenoid precursor, isopentenyl diphosphate, is a, critical function in all independently living organisms. There are two, major pathways for this synthesis, the non-mevalonate pathway found in, most eubacteria and the mevalonate pathway found in animal cells and a, number of pathogenic bacteria. An early step in this pathway is the, condensation of acetyl-CoA and acetoacetyl-CoA into HMG-CoA, catalyzed by, the enzyme HMG-CoA synthase. To explore the possibility of a small, molecule inhibitor of the enzyme functioning as a non-cell wall, antibiotic, the structure of HMG-CoA synthase from Enterococcus faecalis, (MVAS) was determined by selenomethionine MAD phasing to 2.4 A and the, enzyme complexed with its second substrate, acetoacetyl-CoA, to 1.9 A., These structures show that HMG-CoA synthase from Enterococcus is a member, of the family of thiolase fold enzymes and, while similar to the recently, published HMG-CoA synthase structures from Staphylococcus aureus, exhibit, significant differences in the structure of the C-terminal domain. The, acetoacetyl-CoA binary structure demonstrates reduced coenzyme A and, acetoacetate covalently bound to the active site cysteine through a, thioester bond. This is consistent with the kinetics of the reaction that, have shown acetoacetyl-CoA to be a potent inhibitor of the overall, reaction, and provides a starting point in the search for a small molecule, inhibitor.
+<StructureSection load='1ysl' size='340' side='right'caption='[[1ysl]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[1ysl]] is a 2 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=1YSL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1YSL 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]] 1.9&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AAE:ACETOACETIC+ACID'>AAE</scene>, <scene name='pdbligand=COA:COENZYME+A'>COA</scene>, <scene name='pdbligand=CSD:3-SULFINOALANINE'>CSD</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=1ysl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1ysl OCA], [https://pdbe.org/1ysl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1ysl RCSB], [https://www.ebi.ac.uk/pdbsum/1ysl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1ysl ProSAT]</span></td></tr>
+</table>
+== Function ==
+[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>
+== Evolutionary Conservation ==
+[[Image:Consurf_key_small.gif|200px|right]]
+Check<jmol>
+  <jmolCheckbox>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ys/1ysl_consurf.spt"</scriptWhenChecked>
+    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
+    <text>to colour the structure by Evolutionary Conservation</text>
+  </jmolCheckbox>
+</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1ysl ConSurf].
+<div style="clear:both"></div>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Biosynthesis of the isoprenoid precursor, isopentenyl diphosphate, is a critical function in all independently living organisms. There are two major pathways for this synthesis, the non-mevalonate pathway found in most eubacteria and the mevalonate pathway found in animal cells and a number of pathogenic bacteria. An early step in this pathway is the condensation of acetyl-CoA and acetoacetyl-CoA into HMG-CoA, catalyzed by the enzyme HMG-CoA synthase. To explore the possibility of a small molecule inhibitor of the enzyme functioning as a non-cell wall antibiotic, the structure of HMG-CoA synthase from Enterococcus faecalis (MVAS) was determined by selenomethionine MAD phasing to 2.4 A and the enzyme complexed with its second substrate, acetoacetyl-CoA, to 1.9 A. These structures show that HMG-CoA synthase from Enterococcus is a member of the family of thiolase fold enzymes and, while similar to the recently published HMG-CoA synthase structures from Staphylococcus aureus, exhibit significant differences in the structure of the C-terminal domain. The acetoacetyl-CoA binary structure demonstrates reduced coenzyme A and acetoacetate covalently bound to the active site cysteine through a thioester bond. This is consistent with the kinetics of the reaction that have shown acetoacetyl-CoA to be a potent inhibitor of the overall reaction, and provides a starting point in the search for a small molecule inhibitor.
-==About this Structure==
+X-ray crystal structures of HMG-CoA synthase from Enterococcus faecalis and a complex with its second substrate/inhibitor acetoacetyl-CoA.,Steussy CN, Vartia AA, Burgner JW 2nd, Sutherlin A, Rodwell VW, Stauffacher CV Biochemistry. 2005 Nov 1;44(43):14256-67. PMID:16245942<ref>PMID:16245942</ref>
-YSL is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Enterococcus_faecalis Enterococcus faecalis] with SO4, COA, AAE and GOL as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1YSL OCA].
-==Reference==
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-X-ray crystal structures of HMG-CoA synthase from Enterococcus faecalis and a complex with its second substrate/inhibitor acetoacetyl-CoA., Steussy CN, Vartia AA, Burgner JW 2nd, Sutherlin A, Rodwell VW, Stauffacher CV, Biochemistry. 2005 Nov 1;44(43):14256-67. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=16245942 16245942]
+</div>
+<div class="pdbe-citations 1ysl" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
 [[Category: Enterococcus faecalis]]
-[[Category: Hydroxymethylglutaryl-CoA synthase]]
+[[Category: Large Structures]]
-[[Category: Single protein]]
+[[Category: Burgner II JW]]
-[[Category: II, J.W.Burgner.]]
+[[Category: Rodwell VW]]
-[[Category: Rodwell, V.W.]]
+[[Category: Stauffacher CV]]
-[[Category: Stauffacher, C.V.]]
+[[Category: Steussy CN]]
-[[Category: Steussy, C.N.]]
+[[Category: Sutherlin A]]
-[[Category: Sutherlin, A.]]
+[[Category: Vartia AA]]
-[[Category: Vartia, A.A.]]
-[[Category: AAE]]
-[[Category: COA]]
-[[Category: GOL]]
-[[Category: SO4]]
-[[Category: coenzymea]]
-[[Category: thiolase family]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Sun Nov 25 04:33:14 2007''