2px6
From Proteopedia
(New page: 200px<br /> <applet load="2px6" size="450" color="white" frame="true" align="right" spinBox="true" caption="2px6, resolution 2.30Å" /> '''Crystal structure o...) |
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| - | [[Image:2px6. | + | [[Image:2px6.jpg|left|200px]]<br /><applet load="2px6" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="2px6" size=" | + | |
caption="2px6, resolution 2.30Å" /> | caption="2px6, resolution 2.30Å" /> | ||
'''Crystal structure of the thioesterase domain of human fatty acid synthase inhibited by Orlistat'''<br /> | '''Crystal structure of the thioesterase domain of human fatty acid synthase inhibited by Orlistat'''<br /> | ||
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==Overview== | ==Overview== | ||
Human fatty acid synthase (FAS) is uniquely expressed at high levels in, many tumor types. Pharmacological inhibition of FAS therefore represents, an important therapeutic opportunity. The drug Orlistat, which has been, approved by the US Food and Drug Administration, inhibits FAS, induces, tumor cell-specific apoptosis and inhibits the growth of prostate tumor, xenografts. We determined the 2.3-A-resolution crystal structure of the, thioesterase domain of FAS inhibited by Orlistat. Orlistat was captured in, the active sites of two thioesterase molecules as a stable acyl-enzyme, intermediate and as the hydrolyzed product. The details of these, interactions reveal the molecular basis for inhibition and suggest a, mechanism for acyl-chain length discrimination during the FAS catalytic, cycle. Our findings provide a foundation for the development of new cancer, drugs that target FAS. | Human fatty acid synthase (FAS) is uniquely expressed at high levels in, many tumor types. Pharmacological inhibition of FAS therefore represents, an important therapeutic opportunity. The drug Orlistat, which has been, approved by the US Food and Drug Administration, inhibits FAS, induces, tumor cell-specific apoptosis and inhibits the growth of prostate tumor, xenografts. We determined the 2.3-A-resolution crystal structure of the, thioesterase domain of FAS inhibited by Orlistat. Orlistat was captured in, the active sites of two thioesterase molecules as a stable acyl-enzyme, intermediate and as the hydrolyzed product. The details of these, interactions reveal the molecular basis for inhibition and suggest a, mechanism for acyl-chain length discrimination during the FAS catalytic, cycle. Our findings provide a foundation for the development of new cancer, drugs that target FAS. | ||
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| - | ==Disease== | ||
| - | Known diseases associated with this structure: Autoimmune lymphoproliferative syndrome OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=134637 134637]], Autoimmune lymphoproliferative syndrome, type IA OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=134637 134637]], Squamous cell carcinoma, burn scar-related, somatic OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=134637 134637]] | ||
==About this Structure== | ==About this Structure== | ||
| - | 2PX6 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 DH9 and DTT as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Fatty-acid_synthase Fatty-acid synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.1.85 2.3.1.85] Full crystallographic information is available from [http:// | + | 2PX6 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=DH9:'>DH9</scene> and <scene name='pdbligand=DTT:'>DTT</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Fatty-acid_synthase Fatty-acid synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.1.85 2.3.1.85] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2PX6 OCA]. |
==Reference== | ==Reference== | ||
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[[Category: thioesaterse domain]] | [[Category: thioesaterse domain]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 14:08:39 2008'' |
Revision as of 12:08, 23 January 2008
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Crystal structure of the thioesterase domain of human fatty acid synthase inhibited by Orlistat
Overview
Human fatty acid synthase (FAS) is uniquely expressed at high levels in, many tumor types. Pharmacological inhibition of FAS therefore represents, an important therapeutic opportunity. The drug Orlistat, which has been, approved by the US Food and Drug Administration, inhibits FAS, induces, tumor cell-specific apoptosis and inhibits the growth of prostate tumor, xenografts. We determined the 2.3-A-resolution crystal structure of the, thioesterase domain of FAS inhibited by Orlistat. Orlistat was captured in, the active sites of two thioesterase molecules as a stable acyl-enzyme, intermediate and as the hydrolyzed product. The details of these, interactions reveal the molecular basis for inhibition and suggest a, mechanism for acyl-chain length discrimination during the FAS catalytic, cycle. Our findings provide a foundation for the development of new cancer, drugs that target FAS.
About this Structure
2PX6 is a Single protein structure of sequence from Homo sapiens with and as ligands. Active as Fatty-acid synthase, with EC number 2.3.1.85 Full crystallographic information is available from OCA.
Reference
Crystal structure of the thioesterase domain of human fatty acid synthase inhibited by Orlistat., Pemble CW 4th, Johnson LC, Kridel SJ, Lowther WT, Nat Struct Mol Biol. 2007 Aug;14(8):704-9. Epub 2007 Jul 8. PMID:17618296
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