1mx1

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spinqualitylabelsall models 1mx1, resolution 2.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Crystal Structure of Human Liver Carboxylesterase in complex with tacrine

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

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.

Disease

Known disease associated with this structure: Monocyte carboxylesterase deficiency (1) OMIM:[114835]

About this Structure

1MX1 is a Single protein structure of sequence from Homo sapiens with NAG, SIA and THA as ligands. Active as Carboxylesterase, with EC number 3.1.1.1 Full crystallographic information is available from OCA.

Reference

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

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