Crystal structure of human carboxylesterase 1 complexed with the Alzheimer's drug tacrine: from binding promiscuity to selective inhibition.
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.
Department of Chemistry, School of Dentistry, University of North Carolina, Chapel Hill, 27599, USA.
Sompop
S
Bencharit
Christopher L
CL
Morton
Janice L
JL
Hyatt
Peter
P
Kuhn
Mary K
MK
Danks
Philip M
PM
Potter
Matthew R
MR
Redinbo
D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D043182:Carboxylesterase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D002384:Catalysis; D018360:Crystallography, X-Ray; D004583:Electrons; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D013619:Tacrine / Q000737:chemistry* / Q000378:metabolism; D014101:Torpedo
D004791:Enzyme Inhibitors; D013619:Tacrine; D043182:Carboxylesterase; D000110:Acetylcholinesterase