1s64
From Proteopedia
(New page: 200px<br /><applet load="1s64" size="450" color="white" frame="true" align="right" spinBox="true" caption="1s64, resolution 2.55Å" /> '''Rat protein geranylg...) |
|||
| Line 1: | Line 1: | ||
| - | [[Image:1s64.gif|left|200px]]<br /><applet load="1s64" size=" | + | [[Image:1s64.gif|left|200px]]<br /><applet load="1s64" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1s64, resolution 2.55Å" /> | caption="1s64, resolution 2.55Å" /> | ||
'''Rat protein geranylgeranyltransferase type-I complexed with L-778,123 and a sulfate anion'''<br /> | '''Rat protein geranylgeranyltransferase type-I complexed with L-778,123 and a sulfate anion'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Many signal transduction proteins that control growth, differentiation, and transformation, including Ras GTPase family members, require the | + | 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== | ||
| - | 1S64 is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus] with ZN, CL, SO4, 778 and MES as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Protein_geranylgeranyltransferase_type_I Protein geranylgeranyltransferase type I], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.5.1.59 2.5.1.59] Full crystallographic information is available from [http:// | + | 1S64 is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus] with <scene name='pdbligand=ZN:'>ZN</scene>, <scene name='pdbligand=CL:'>CL</scene>, <scene name='pdbligand=SO4:'>SO4</scene>, <scene name='pdbligand=778:'>778</scene> and <scene name='pdbligand=MES:'>MES</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Protein_geranylgeranyltransferase_type_I Protein geranylgeranyltransferase type I], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.5.1.59 2.5.1.59] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1S64 OCA]. |
==Reference== | ==Reference== | ||
| Line 14: | Line 14: | ||
[[Category: Protein geranylgeranyltransferase type I]] | [[Category: Protein geranylgeranyltransferase type I]] | ||
[[Category: Rattus norvegicus]] | [[Category: Rattus norvegicus]] | ||
| - | [[Category: Beese, L | + | [[Category: Beese, L S.]] |
| - | [[Category: Long, S | + | [[Category: Long, S B.]] |
| - | [[Category: Reid, T | + | [[Category: Reid, T S.]] |
[[Category: 778]] | [[Category: 778]] | ||
[[Category: CL]] | [[Category: CL]] | ||
| Line 29: | Line 29: | ||
[[Category: protein prenylation]] | [[Category: protein prenylation]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:58:25 2008'' |
Revision as of 12:58, 21 February 2008
|
Rat protein geranylgeranyltransferase type-I complexed with L-778,123 and a sulfate anion
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
1S64 is a Protein complex structure of sequences from Rattus norvegicus with , , , and as ligands. Active as Protein geranylgeranyltransferase type I, with EC number 2.5.1.59 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 Thu Feb 21 14:58:25 2008
