3V4N
The Biochemical and Structural Basis for Inhibition of Enterococcus faecalis HMG-CoA Synthatse, mvaS, by Hymeglusin
Summary for 3V4N
| Entry DOI | 10.2210/pdb3v4n/pdb |
| Related | 3V4X |
| Descriptor | HMG-CoA synthase, 2-[BIS-(2-HYDROXY-ETHYL)-AMINO]-2-HYDROXYMETHYL-PROPANE-1,3-DIOL (3 entities in total) |
| Functional Keywords | hydroxymethylglutaryl-coa synthase, nitrosylation, transferase-inhibitor complex, transferase/inhibitor |
| Biological source | Enterococcus faecalis |
| Total number of polymer chains | 4 |
| Total formula weight | 170712.96 |
| Authors | Skaff, D.A.,Ramyar, K.X.,McWhorter, W.J.,Geisbrecht, B.V.,Miziorko, H.M. (deposition date: 2011-12-15, release date: 2012-04-25, Last modification date: 2024-10-16) |
| Primary citation | Skaff, D.A.,Ramyar, K.X.,McWhorter, W.J.,Barta, M.L.,Geisbrecht, B.V.,Miziorko, H.M. Biochemical and structural basis for inhibition of Enterococcus faecalis hydroxymethylglutaryl-CoA synthase, mvaS, by hymeglusin. Biochemistry, 51:4713-4722, 2012 Cited by PubMed Abstract: Hymeglusin (1233A, F244, L-659-699) is established as a specific β-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 Å) 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. PubMed: 22510038DOI: 10.1021/bi300037k PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.6 Å) |
Structure validation
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