Structural basis for the design of potent and species-specific inhibitors of 3-hydroxy-3-methylglutaryl CoA synthases.
3-Hydroxy-3-methylglutaryl CoA synthase (HMGS) catalyzes the first committed step in the mevalonate metabolic pathway for isoprenoid biosynthesis and serves as an alternative target for cholesterol-lowering and antibiotic drugs. We have determined a previously undescribed crystal structure of a eukaryotic HMGS bound covalently to a potent and specific inhibitor F-244 [(E,E)-11-[3-(hydroxymethyl)-4-oxo-2-oxytanyl]-3,5,7-trimethyl-2,4-undecadienenoic acid]. Given the accessibility of synthetic analogs of the F-244 natural product, this inhibited eukaryotic HMGS structure serves as a necessary starting point for structure-based methods that may improve the potency and species-specific selectivity of the next generation of F-244 analogs designed to target particular eukaryotic and prokaryotic HMGS.
Pojer
Florence
F
Howard Hughes Medical Institute, The Jack H. Skirball Center for Chemical Biology and Proteomics, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
Ferrer
Jean-Luc
JL
Richard
Stéphane B
SB
Nagegowda
Dinesh A
DA
Chye
Mee-Len
ML
Bach
Thomas J
TJ
Noel
Joseph P
JP
D001665:Binding Sites; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006904:Hydroxymethylglutaryl-CoA Synthase / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D007783:Lactones / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009149:Mustard Plant / Q000201:enzymology*; D010940:Plant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D005231:Fatty Acids, Unsaturated; D007783:Lactones; D010940:Plant Proteins; C054282:antibiotic 1233A; D006904:Hydroxymethylglutaryl-CoA Synthase