Crystal structure of human carboxylesterase 1 complexed with the Alzheimer's drug tacrine: from binding promiscuity to selective inhibition.

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Bencharit S, Morton CL, Hyatt JL, Kuhn P, Danks MK, Potter PM, Redinbo MR

Crystal structure of human carboxylesterase 1 complexed with the Alzheimer's drug tacrine: from binding promiscuity to selective inhibition.

Chem Biol. 2003 Apr;10(4):341-9.

PubMed ID

12725862 [ View in PubMed

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Abstract

Human 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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Tacrine	Liver carboxylesterase 1	Protein	Humans	Unknown	Not Available	Details

Polypeptides

Name	UniProt ID
Liver carboxylesterase 1	P23141	Details

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Tacrine	Acetylcholinesterase	Ki (nM)	6.9	7.4	22	Details
Tacrine	Liver carboxylesterase 1	Ki (nM)	>100000	7.4	22	Details