1ya4
From Proteopedia
(New page: 200px<br /> <applet load="1ya4" size="450" color="white" frame="true" align="right" spinBox="true" caption="1ya4, resolution 3.20Å" /> '''Crystal Structure o...) |
|||
| Line 1: | Line 1: | ||
| - | [[Image:1ya4.gif|left|200px]]<br /> | + | [[Image:1ya4.gif|left|200px]]<br /><applet load="1ya4" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="1ya4" size=" | + | |
caption="1ya4, resolution 3.20Å" /> | caption="1ya4, resolution 3.20Å" /> | ||
'''Crystal Structure of Human Liver Carboxylesterase 1 in complex with tamoxifen'''<br /> | '''Crystal Structure of Human Liver Carboxylesterase 1 in complex with tamoxifen'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Human carboxylesterase 1 (hCE1) exhibits broad substrate specificity and | + | 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. |
==Disease== | ==Disease== | ||
| Line 11: | Line 10: | ||
==About this Structure== | ==About this Structure== | ||
| - | 1YA4 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with NAG, SIA, SO4 and CTX as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Full crystallographic information is available from [http:// | + | 1YA4 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=NAG:'>NAG</scene>, <scene name='pdbligand=SIA:'>SIA</scene>, <scene name='pdbligand=SO4:'>SO4</scene> and <scene name='pdbligand=CTX:'>CTX</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1YA4 OCA]. |
==Reference== | ==Reference== | ||
| Line 19: | Line 18: | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Bencharit, S.]] | [[Category: Bencharit, S.]] | ||
| - | [[Category: Edwards, C | + | [[Category: Edwards, C C.]] |
| - | [[Category: Fleming, C | + | [[Category: Fleming, C D.]] |
| - | [[Category: Howard-Williams, E | + | [[Category: Howard-Williams, E L.]] |
| - | [[Category: Hyatt, J | + | [[Category: Hyatt, J L.]] |
| - | [[Category: Morton, C | + | [[Category: Morton, C L.]] |
| - | [[Category: Potter, P | + | [[Category: Potter, P M.]] |
| - | [[Category: Redinbo, M | + | [[Category: Redinbo, M R.]] |
[[Category: CTX]] | [[Category: CTX]] | ||
[[Category: NAG]] | [[Category: NAG]] | ||
| Line 33: | Line 32: | ||
[[Category: tamoxifen complex]] | [[Category: tamoxifen complex]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:03:13 2008'' |
Revision as of 14:03, 21 February 2008
|
Crystal Structure of Human Liver Carboxylesterase 1 in complex with tamoxifen
Contents |
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.
Disease
Known disease associated with this structure: Monocyte carboxylesterase deficiency (1) OMIM:[114835]
About this Structure
1YA4 is a Single protein structure of sequence from Homo sapiens with , , and as ligands. Active as Carboxylesterase, with EC number 3.1.1.1 Full crystallographic information is available from OCA.
Reference
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 Thu Feb 21 16:03:13 2008
