Affordable Access

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

Authors
  • Bencharit, Sompop
  • Morton, Christopher L
  • Hyatt, Janice L
  • Kuhn, Peter
  • Danks, Mary K
  • Potter, Philip M
  • Redinbo, Matthew R
Type
Published Article
Journal
Chemistry & Biology
Publisher
Elsevier
Publication Date
Apr 01, 2003
Volume
10
Issue
4
Pages
341–349
Identifiers
PMID: 12725862
Source
Medline
License
Unknown

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.

Report this publication

Statistics

Seen <100 times