1s63
From Proteopedia
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[[Image:1s63.gif|left|200px]] | [[Image:1s63.gif|left|200px]] | ||
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'''Human protein farnesyltransferase complexed with L-778,123 and FPP''' | '''Human protein farnesyltransferase complexed with L-778,123 and FPP''' | ||
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[[Category: Casey, P J.]] | [[Category: Casey, P J.]] | ||
[[Category: Long, S B.]] | [[Category: Long, S B.]] | ||
| - | [[Category: | + | [[Category: Caax]] |
| - | [[Category: | + | [[Category: Cancer]] |
| - | [[Category: | + | [[Category: Farnesyltransferase]] |
| - | [[Category: | + | [[Category: Ftase]] |
| - | [[Category: | + | [[Category: Fti]] |
| - | [[Category: | + | [[Category: Geranylgeranyltransferase]] |
| - | [[Category: | + | [[Category: Inhibitor]] |
| - | [[Category: | + | [[Category: Lipid modification]] |
| - | [[Category: | + | [[Category: Protein prenylation]] |
| - | [[Category: | + | [[Category: Ra]] |
| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 08:20:56 2008'' | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | |
Revision as of 05:20, 3 May 2008
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. 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 Page seeded by OCA on Sat May 3 08:20:56 2008
