1YSL

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

Summary for 1YSL

• Entry DOI: 10.2210/pdb1ysl/pdb
• Related: 1x9e
• Descriptor: HMG-CoA synthase, SULFATE ION, GLYCEROL, ... (7 entities in total)
• Functional Keywords: thiolase family, coenzymea, lyase
• Biological source: Enterococcus faecalis; More
• Total number of polymer chains: 2
• Total formula weight: 89829.64

Authors

Steussy, C.N.,Vartia, A.A.,Burgner II, J.W.,Sutherlin, A.,Rodwell, V.W.,Stauffacher, C.V. (deposition date: 2005-02-08, release date: 2005-11-08, Last modification date: 2024-12-25)

Primary citation

Steussy, C.N.,Vartia, A.A.,Burgner II, J.W.,Sutherlin, A.,Rodwell, V.W.,Stauffacher, C.V.
X-ray Crystal Structures of HMG-CoA Synthase from Enterococcus faecalis and a Complex with Its Second Substrate/Inhibitor Acetoacetyl-CoA.
Biochemistry, 44:14256-14267, 2005

PubMed Abstract: 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.

PubMed: 16245942
DOI: 10.1021/bi051487x

Experimental method

X-RAY DIFFRACTION (1.9 Å)