1ya8: Difference between revisions
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|PDB= 1ya8 |SIZE=350|CAPTION= <scene name='initialview01'>1ya8</scene>, resolution 3.00Å | |PDB= 1ya8 |SIZE=350|CAPTION= <scene name='initialview01'>1ya8</scene>, resolution 3.00Å | ||
|SITE= | |SITE= | ||
|LIGAND= | |LIGAND= <scene name='pdbligand=MVB:(1S,7S,8S,8AR)-1,2,3,7,8,8A-HEXAHYDRO-7-METHYL-8-[2-[(2R,4R)-TETRAHYDRO-4-HY+DROXY-6-OXO-2H-PYRAN-2-YL]ETHYL]-1-NAPHTHALENOL'>MVB</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=SIA:O-SIALIC+ACID'>SIA</scene>, <scene name='pdbligand=SMB:2-METHYLBUTANOIC+ACID'>SMB</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene> | ||
|ACTIVITY= [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] | |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> | ||
|GENE= | |GENE= | ||
|DOMAIN= | |||
|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> | |||
}} | }} | ||
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==Overview== | ==Overview== | ||
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. | 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 Structure== | ==About this Structure== | ||
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[[Category: Potter, P M.]] | [[Category: Potter, P M.]] | ||
[[Category: Redinbo, M R.]] | [[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 | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 01:00:45 2008'' | ||