1mx1
Crystal Structure of Human Liver Carboxylesterase in complex with tacrine
Structural highlights
FunctionEST1_HUMAN Involved in the detoxification of xenobiotics and in the activation of ester and amide prodrugs. Hydrolyzes aromatic and aliphatic esters, but has no catalytic activity toward amides or a fatty acyl-CoA ester. Hydrolyzes the methyl ester group of cocaine to form benzoylecgonine. Catalyzes the transesterification of cocaine to form cocaethylene. Displays fatty acid ethyl ester synthase activity, catalyzing the ethyl esterification of oleic acid to ethyloleate.[1] [2] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedHuman carboxylesterase 1 (hCE1) is a broad-spectrum bioscavenger that plays important roles in narcotic metabolism, clinical prodrug activation, and the processing of fatty acid and cholesterol derivatives. We determined the 2.4 A crystal structure of hCE1 in complex with tacrine, the first drug approved for treating Alzheimer's disease, and compare this structure to the Torpedo californica acetylcholinesterase (AcChE)-tacrine complex. Tacrine binds in multiple orientations within the catalytic gorge of hCE1, while it stacks in the smaller AcChE active site between aromatic side chains. Our results show that hCE1's promiscuous action on distinct substrates is enhanced by its ability to interact with ligands in multiple orientations at once. Further, we use our structure to identify tacrine derivatives that act as low-micromolar inhibitors of hCE1 and may provide new avenues for treating narcotic abuse and cholesterol-related diseases. Crystal structure of human carboxylesterase 1 complexed with the Alzheimer's drug tacrine: from binding promiscuity to selective inhibition.,Bencharit S, Morton CL, Hyatt JL, Kuhn P, Danks MK, Potter PM, Redinbo MR Chem Biol. 2003 Apr;10(4):341-9. PMID:12725862[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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