1sa4
From Proteopedia
(New page: 200px<br /> <applet load="1sa4" size="450" color="white" frame="true" align="right" spinBox="true" caption="1sa4, resolution 2.10Å" /> '''human protein farne...) |
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| - | [[Image:1sa4.gif|left|200px]]<br /> | + | [[Image:1sa4.gif|left|200px]]<br /><applet load="1sa4" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="1sa4" size=" | + | |
caption="1sa4, resolution 2.10Å" /> | caption="1sa4, resolution 2.10Å" /> | ||
'''human protein farnesyltransferase complexed with FPP and R115777'''<br /> | '''human protein farnesyltransferase complexed with FPP and R115777'''<br /> | ||
==Overview== | ==Overview== | ||
| - | The search for new cancer therapeutics has identified protein | + | The search for new cancer therapeutics has identified protein farnesyltransferase (FTase) as a promising drug target. This enzyme attaches isoprenoid lipids to signal transduction proteins involved in growth and differentiation. The two FTase inhibitors (FTIs), R115777 (tipifarnib/Zarnestra) and BMS-214662, have undergone evaluation as cancer therapeutics in phase I and II clinical trials. R115777 has been evaluated in phase III clinical trials and shows indications for the treatment of blood and breast malignancies. Here we present crystal structures of R115777 and BMS-214662 complexed with mammalian FTase. These structures illustrate the molecular mechanism of inhibition and selectivity toward FTase over the related enzyme, protein geranylgeranyltransferase type I (GGTase-I). These results, combined with previous biochemical and structural analyses, identify features of FTase that could be exploited to modulate inhibitor potency and specificity and should aid in the continued development of FTIs as therapeutics for the treatment of cancer and parasitic infections. |
==About this Structure== | ==About this Structure== | ||
| - | 1SA4 is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with SUC, ZN, FPP and JAN as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Protein_farnesyltransferase Protein farnesyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.5.1.58 2.5.1.58] Full crystallographic information is available from [http:// | + | 1SA4 is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=SUC:'>SUC</scene>, <scene name='pdbligand=ZN:'>ZN</scene>, <scene name='pdbligand=FPP:'>FPP</scene> and <scene name='pdbligand=JAN:'>JAN</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Protein_farnesyltransferase Protein farnesyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.5.1.58 2.5.1.58] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1SA4 OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Protein complex]] | [[Category: Protein complex]] | ||
[[Category: Protein farnesyltransferase]] | [[Category: Protein farnesyltransferase]] | ||
| - | [[Category: Beese, L | + | [[Category: Beese, L S.]] |
| - | [[Category: Reid, T | + | [[Category: Reid, T S.]] |
[[Category: FPP]] | [[Category: FPP]] | ||
[[Category: JAN]] | [[Category: JAN]] | ||
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[[Category: zarnestra]] | [[Category: zarnestra]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:59:25 2008'' |
Revision as of 12:59, 21 February 2008
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human protein farnesyltransferase complexed with FPP and R115777
Overview
The search for new cancer therapeutics has identified protein farnesyltransferase (FTase) as a promising drug target. This enzyme attaches isoprenoid lipids to signal transduction proteins involved in growth and differentiation. The two FTase inhibitors (FTIs), R115777 (tipifarnib/Zarnestra) and BMS-214662, have undergone evaluation as cancer therapeutics in phase I and II clinical trials. R115777 has been evaluated in phase III clinical trials and shows indications for the treatment of blood and breast malignancies. Here we present crystal structures of R115777 and BMS-214662 complexed with mammalian FTase. These structures illustrate the molecular mechanism of inhibition and selectivity toward FTase over the related enzyme, protein geranylgeranyltransferase type I (GGTase-I). These results, combined with previous biochemical and structural analyses, identify features of FTase that could be exploited to modulate inhibitor potency and specificity and should aid in the continued development of FTIs as therapeutics for the treatment of cancer and parasitic infections.
About this Structure
1SA4 is a Protein complex structure of sequences from Homo sapiens with , , and as ligands. Active as Protein farnesyltransferase, with EC number 2.5.1.58 Full crystallographic information is available from OCA.
Reference
Crystal structures of the anticancer clinical candidates R115777 (Tipifarnib) and BMS-214662 complexed with protein farnesyltransferase suggest a mechanism of FTI selectivity., Reid TS, Beese LS, Biochemistry. 2004 Jun 8;43(22):6877-84. PMID:15170324
Page seeded by OCA on Thu Feb 21 14:59:25 2008
Categories: Homo sapiens | Protein complex | Protein farnesyltransferase | Beese, L S. | Reid, T S. | FPP | JAN | SUC | ZN | Caax | Cancer | Clinical candidate | Farnesyl transferase | Farnesyltransferase | Ftase | Fti | Inhibitor | Lipid modification | Protein prenylation | R115777 | Ras | Tipifarnib | Tumor regression | Zarnestra
