1YA8

Crystal Structure of Human Liver Carboxylesterase in complex with cleavage products of Mevastatin

Summary for 1YA8

• Entry DOI: 10.2210/pdb1ya8/pdb
• Related: 1MX1 1MX5 1MX9 1ya4 1yah 1yaj
• Descriptor: CES1 protein, 2-acetamido-2-deoxy-beta-D-glucopyranose, N-acetyl-alpha-neuraminic acid, ... (7 entities in total)
• Functional Keywords: hydrolase, carboxylesterase, mevastatin
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 3
• Total formula weight: 179205.81

Authors

Fleming, C.D.,Bencharit, S.,Edwards, C.C.,Hyatt, J.L.,Morton, C.L.,Howard-Williams, E.L.,Potter, P.M.,Redinbo, M.R. (deposition date: 2004-12-17, release date: 2005-08-02, Last modification date: 2024-11-13)

Primary citation

Fleming, C.D.,Bencharit, S.,Edwards, C.C.,Hyatt, J.L.,Tsurkan, L.,Bai, F.,Fraga, C.,Morton, C.L.,Howard-Williams, E.L.,Potter, P.M.,Redinbo, M.R.
Structural insights into drug processing by human carboxylesterase 1: tamoxifen, mevastatin, and inhibition by benzil.
J.Mol.Biol., 352:165-177, 2005

PubMed Abstract: Human carboxylesterase 1 (hCE1) exhibits broad substrate specificity and is involved in xenobiotic processing and endobiotic metabolism. We present and analyze crystal structures of hCE1 in complexes with the cholesterol-lowering drug mevastatin, the breast cancer drug tamoxifen, the fatty acyl ethyl ester (FAEE) analogue ethyl acetate, and the novel hCE1 inhibitor benzil. We find that mevastatin does not appear to be a substrate for hCE1, and instead acts as a partially non-competitive inhibitor of the enzyme. Similarly, we show that tamoxifen is a low micromolar, partially non-competitive inhibitor of hCE1. Further, we describe the structural basis for the inhibition of hCE1 by the nanomolar-affinity dione benzil, which acts by forming both covalent and non-covalent complexes with the enzyme. Our results provide detailed insights into the catalytic and non-catalytic processing of small molecules by hCE1, and suggest that the efficacy of clinical drugs may be modulated by targeted hCE1 inhibitors.

PubMed: 16081098
DOI: 10.1016/j.jmb.2005.07.016

Experimental method

X-RAY DIFFRACTION (3 Å)