1s63

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(New page: 200px<br /> <applet load="1s63" size="450" color="white" frame="true" align="right" spinBox="true" caption="1s63, resolution 1.90&Aring;" /> '''Human protein farne...)
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<applet load="1s63" size="450" color="white" frame="true" align="right" spinBox="true"
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'''Human protein farnesyltransferase complexed with L-778,123 and FPP'''<br />
'''Human protein farnesyltransferase complexed with L-778,123 and FPP'''<br />
==Overview==
==Overview==
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Many signal transduction proteins that control growth, differentiation, and transformation, including Ras GTPase family members, require the, covalent attachment of a lipid group by protein farnesyltransferase, (FTase) or protein geranylgeranyltransferase type-I (GGTase-I) for proper, function and for the transforming activity of oncogenic mutants. FTase, inhibitors are a new class of potential cancer therapeutics under, evaluation in human clinical trials. Here, we present crystal structures, of the clinical candidate L-778,123 complexed with mammalian FTase and, complexed with the related GGTase-I enzyme. Although FTase and GGTase-I, have very similar active sites, L-778,123 adopts different binding modes, in the two enzymes; in FTase, L-778,123 is competitive with the protein, substrate, whereas in GGTase-I, L-778,123 is competitive with the lipid, substrate and inhibitor binding is synergized by tetrahedral anions. A, comparison of these complexes reveals that small differences in protein, structure can dramatically affect inhibitor binding and selectivity. These, structures should facilitate the design of more specific inhibitors toward, FTase or GGTase-I. Finally, the binding of a drug and anion together could, be applicable for developing new classes of inhibitors.
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Many signal transduction proteins that control growth, differentiation, and transformation, including Ras GTPase family members, require the covalent attachment of a lipid group by protein farnesyltransferase (FTase) or protein geranylgeranyltransferase type-I (GGTase-I) for proper function and for the transforming activity of oncogenic mutants. FTase inhibitors are a new class of potential cancer therapeutics under evaluation in human clinical trials. Here, we present crystal structures of the clinical candidate L-778,123 complexed with mammalian FTase and complexed with the related GGTase-I enzyme. Although FTase and GGTase-I have very similar active sites, L-778,123 adopts different binding modes in the two enzymes; in FTase, L-778,123 is competitive with the protein substrate, whereas in GGTase-I, L-778,123 is competitive with the lipid substrate and inhibitor binding is synergized by tetrahedral anions. A comparison of these complexes reveals that small differences in protein structure can dramatically affect inhibitor binding and selectivity. These structures should facilitate the design of more specific inhibitors toward FTase or GGTase-I. Finally, the binding of a drug and anion together could be applicable for developing new classes of inhibitors.
==About this Structure==
==About this Structure==
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1S63 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 778 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://ispc.weizmann.ac.il/oca-bin/ocashort?id=1S63 OCA].
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1S63 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=778:'>778</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=1S63 OCA].
==Reference==
==Reference==
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[[Category: Protein complex]]
[[Category: Protein complex]]
[[Category: Protein farnesyltransferase]]
[[Category: Protein farnesyltransferase]]
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[[Category: Beese, L.S.]]
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[[Category: Beese, L S.]]
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[[Category: Casey, P.J.]]
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[[Category: Casey, P J.]]
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[[Category: Long, S.B.]]
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[[Category: Long, S B.]]
[[Category: 778]]
[[Category: 778]]
[[Category: FPP]]
[[Category: FPP]]
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[[Category: ras]]
[[Category: ras]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 19:10:47 2007''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:58:21 2008''

Revision as of 12:58, 21 February 2008

Image:1s63.gif

1s63, resolution 1.90Å

Drag the structure with the mouse to rotate

Human protein farnesyltransferase complexed with L-778,123 and FPP

Overview

Many signal transduction proteins that control growth, differentiation, and transformation, including Ras GTPase family members, require the covalent attachment of a lipid group by protein farnesyltransferase (FTase) or protein geranylgeranyltransferase type-I (GGTase-I) for proper function and for the transforming activity of oncogenic mutants. FTase inhibitors are a new class of potential cancer therapeutics under evaluation in human clinical trials. Here, we present crystal structures of the clinical candidate L-778,123 complexed with mammalian FTase and complexed with the related GGTase-I enzyme. Although FTase and GGTase-I have very similar active sites, L-778,123 adopts different binding modes in the two enzymes; in FTase, L-778,123 is competitive with the protein substrate, whereas in GGTase-I, L-778,123 is competitive with the lipid substrate and inhibitor binding is synergized by tetrahedral anions. A comparison of these complexes reveals that small differences in protein structure can dramatically affect inhibitor binding and selectivity. These structures should facilitate the design of more specific inhibitors toward FTase or GGTase-I. Finally, the binding of a drug and anion together could be applicable for developing new classes of inhibitors.

About this Structure

1S63 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

Crystallographic analysis reveals that anticancer clinical candidate L-778,123 inhibits protein farnesyltransferase and geranylgeranyltransferase-I by different binding modes., Reid TS, Long SB, Beese LS, Biochemistry. 2004 Jul 20;43(28):9000-8. PMID:15248757

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