PDBsum entry 1x9e

Lyase

PDB id: 1x9e

Contents

Protein chains

383 a.a.

Ligands

SO4 ×4

Waters ×170

References listed in PDB file

Key reference

• Title: X-Ray crystal structures of hmg-Coa synthase from enterococcus faecalis and a complex with its second substrate/inhibitor acetoacetyl-Coa.
• Authors: C.N.Steussy, A.A.Vartia, J.W.Burgner, A.Sutherlin, V.W.Rodwell, C.V.Stauffacher.
• Ref.: Biochemistry, 2005, 44, 14256-14267. [DOI no: 10.1021/bi051487x]
• PubMed id: 16245942

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.