1x9e
From Proteopedia
(New page: 200px<br /><applet load="1x9e" size="450" color="white" frame="true" align="right" spinBox="true" caption="1x9e, resolution 2.40Å" /> '''Crystal structure of...) |
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| - | [[Image:1x9e.jpg|left|200px]]<br /><applet load="1x9e" size=" | + | [[Image:1x9e.jpg|left|200px]]<br /><applet load="1x9e" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1x9e, resolution 2.40Å" /> | caption="1x9e, resolution 2.40Å" /> | ||
'''Crystal structure of HMG-CoA synthase from Enterococcus faecalis'''<br /> | '''Crystal structure of HMG-CoA synthase from Enterococcus faecalis'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Biosynthesis of the isoprenoid precursor, isopentenyl diphosphate, is a | + | 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== | ==About this Structure== | ||
| - | 1X9E 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 as [http://en.wikipedia.org/wiki/ligand ligand]. 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:// | + | 1X9E 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 <scene name='pdbligand=SO4:'>SO4</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. 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://oca.weizmann.ac.il/oca-bin/ocashort?id=1X9E OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Hydroxymethylglutaryl-CoA synthase]] | [[Category: Hydroxymethylglutaryl-CoA synthase]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: II, J | + | [[Category: II, J W.Burgner.]] |
| - | [[Category: Rodwell, V | + | [[Category: Rodwell, V W.]] |
| - | [[Category: Stauffacher, C | + | [[Category: Stauffacher, C V.]] |
| - | [[Category: Steussy, C | + | [[Category: Steussy, C N.]] |
[[Category: Sutherlin, A.]] | [[Category: Sutherlin, A.]] | ||
| - | [[Category: Vartia, A | + | [[Category: Vartia, A A.]] |
[[Category: SO4]] | [[Category: SO4]] | ||
[[Category: thiolase family]] | [[Category: thiolase family]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:52:23 2008'' |
Revision as of 13:52, 21 February 2008
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Crystal structure of HMG-CoA synthase from Enterococcus faecalis
Overview
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
1X9E is a Single protein structure of sequence from Enterococcus faecalis with as ligand. Active as Hydroxymethylglutaryl-CoA synthase, with EC number 2.3.3.10 Full crystallographic information is available from OCA.
Reference
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
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