Abstract
The crystal structure of human 20alpha-hydroxysteroid dehydrogenase (AKR1C1) in ternary complex with the coenzyme NADP (+) and the potent inhibitor 3,5-dichlorosalicylic acid was determined at a resolution of 1.8 A. The inhibitor is held in place by a network of hydrogen bonding interactions with the active site residues Tyr55, His117, and His222. The important role of the nonconserved residues Leu54, His222, Leu306, and Leu308 in inhibitor binding and selectivity was determined by site-directed mutagenesis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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20-alpha-Hydroxysteroid Dehydrogenase / antagonists & inhibitors*
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20-alpha-Hydroxysteroid Dehydrogenase / chemistry
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20-alpha-Hydroxysteroid Dehydrogenase / genetics
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20-alpha-Hydroxysteroid Dehydrogenase / metabolism*
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Binding Sites
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Chlorobenzoates
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Coenzymes / chemistry*
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Coenzymes / metabolism*
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Crystallography, X-Ray
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / pharmacology
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Humans
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Isoenzymes / antagonists & inhibitors
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Isoenzymes / genetics
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Isoenzymes / metabolism
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Models, Molecular
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Mutation / genetics
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Protein Binding
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Protein Structure, Secondary
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Protein Structure, Tertiary
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Salicylates / chemistry*
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Salicylates / pharmacology*
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Structural Homology, Protein
Substances
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Chlorobenzoates
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Coenzymes
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Enzyme Inhibitors
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Isoenzymes
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Salicylates
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20-alpha-Hydroxysteroid Dehydrogenase
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3,5-dichlorosalicylic acid