1ya8: Difference between revisions

Revision as of 16:03, 3 May 2008

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

OverviewOverview

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.

About this StructureAbout this Structure

1YA8 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

ReferenceReference

Structural insights into drug processing by human carboxylesterase 1: tamoxifen, mevastatin, and inhibition by benzil., Fleming CD, Bencharit S, Edwards CC, Hyatt JL, Tsurkan L, Bai F, Fraga C, Morton CL, Howard-Williams EL, Potter PM, Redinbo MR, J Mol Biol. 2005 Sep 9;352(1):165-77. PMID:16081098 Page seeded by OCA on Sat May 3 16:03:57 2008

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OCA

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 [[Image:1ya8.gif|left|200px]]
- {{Structure
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+The line below this paragraph, containing "STRUCTURE_1ya8", creates the "Structure Box" on the page.
-|SITE=
+You may change the PDB parameter (which sets the PDB file loaded into the applet)
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-|ACTIVITY= <span class='plainlinks'>[http://en.wikipedia.org/wiki/Carboxylesterase Carboxylesterase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.1.1 3.1.1.1] </span>
+or leave the SCENE parameter empty for the default display.
-|GENE=
+-->
-|DOMAIN=
+{{STRUCTURE_1ya8|  PDB=1ya8  |  SCENE=  }}
-|RELATEDENTRY=[[1mx1|1MX1]], [[1mx5|1MX5]], [[1mx9|1MX9]], [[1ya4|1ya4]], [[1yah|1yah]], [[1yaj|1yaj]]
-|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1ya8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1ya8 OCA], [http://www.ebi.ac.uk/pdbsum/1ya8 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1ya8 RCSB]</span>
-}}
 '''Crystal Structure of Human Liver Carboxylesterase in complex with cleavage products of Mevastatin'''
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 [[Category: Potter, P M.]]
 [[Category: Redinbo, M R.]]
-[[Category: carboxylesterase]]
+[[Category: Carboxylesterase]]
-[[Category: hydrolase]]
+[[Category: Hydrolase]]
-[[Category: mevastatin]]
+[[Category: Mevastatin]]
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May  3 16:03:57 2008''
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 01:00:45 2008''