Bencharit_2003_Chem.Biol_10_341

Reference

Title : Crystal structure of human carboxylesterase 1 complexed with the Alzheimer's drug tacrine: from binding promiscuity to selective inhibition - Bencharit_2003_Chem.Biol_10_341
Author(s) : Bencharit S , Morton CL , Hyatt JL , Kuhn P , Danks MK , Potter PM , Redinbo MR
Ref : Chemical Biology , 10 :341 , 2003
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.

PubMedSearch : Bencharit_2003_Chem.Biol_10_341
PubMedID: 12725862
Gene_locus related to this paper: human-CES1

Related information

Inhibitor Tacrine
Gene_locus Tacrine    human-CES1
Family Tacrine    human-CES1    Carb_B_Chordata
Structure Tacrine    human-CES1    Carb_B_Chordata    1MX1

Citations formats

Bencharit S, Morton CL, Hyatt JL, Kuhn P, Danks MK, Potter PM, Redinbo MR (2003)
Crystal structure of human carboxylesterase 1 complexed with the Alzheimer's drug tacrine: from binding promiscuity to selective inhibition
Chemical Biology 10 :341

Bencharit S, Morton CL, Hyatt JL, Kuhn P, Danks MK, Potter PM, Redinbo MR (2003)
Chemical Biology 10 :341