1s64
Rat protein geranylgeranyltransferase type-I complexed with L-778,123 and a sulfate anion
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OverviewOverview
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 StructureAbout this Structure
1S64 is a Protein complex structure of sequences from Rattus norvegicus with ZN, CL, SO4, 778 and MES as ligands. Active as Protein geranylgeranyltransferase type I, with EC number 2.5.1.59 Full crystallographic information is available from OCA.
ReferenceReference
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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