Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Binding Sites
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Crystallography, X-Ray
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Enzyme Inhibitors* / chemistry
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Enzyme Inhibitors* / metabolism
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Fatty Acids, Unsaturated* / chemistry
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Fatty Acids, Unsaturated* / metabolism
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Humans
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Hydroxymethylglutaryl-CoA Synthase / antagonists & inhibitors*
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Hydroxymethylglutaryl-CoA Synthase / chemistry*
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Hydroxymethylglutaryl-CoA Synthase / metabolism
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Lactones* / chemistry
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Lactones* / metabolism
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Models, Molecular
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Molecular Sequence Data
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Mustard Plant / enzymology*
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Plant Proteins / antagonists & inhibitors
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Plant Proteins / chemistry
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Plant Proteins / metabolism
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Protein Structure, Tertiary*
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Structure-Activity Relationship
Substances
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Enzyme Inhibitors
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Fatty Acids, Unsaturated
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Lactones
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Plant Proteins
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antibiotic 1233A
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Hydroxymethylglutaryl-CoA Synthase
Associated data
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PDB/2F82
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PDB/2F9A
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PDB/2FA0
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PDB/2FA3