1agp
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THREE-DIMENSIONAL STRUCTURES AND PROPERTIES OF A TRANSFORMING AND A NONTRANSFORMING GLY-12 MUTANT OF P21-H-RAS
OverviewOverview
The three-dimensional structures and biochemical properties of two mutants of the G-domain (residues 1-166) of p21H-ras, p21 (G12D) and p21 (G12P), have been determined in the triphosphate-bound form using guanosine 5'-(beta,gamma-imido)triphosphate (GppNHp). They correspond to the most frequent oncogenic and the only nononcogenic mutation of Gly-12, respectively. The G12D mutation is the only mutant analyzed so far that crystallizes in a space group different from wild type, and the atomic model of the protein shows the most drastic changes of structure around the active site as compared to wild-type p21. This is due to the interactions of the aspartic acid side chain with Tyr-32, Gln-61, and the gamma-phosphate, which result in reduced mobility of these structural elements. The interaction between the carboxylate group of Asp-12 and the gamma-phosphate is mediated by a shared proton, which we show by 31P NMR measurements to exist in solution as well. The structure of p21 (G12P) is remarkably similar to that of wild-type p21 in the active site, including the position of the nucleophilic water. The pyrrolidine ring of Pro-12 points outward and seems to be responsible for the weaker affinity toward GAP (GTPase-activating protein) and the failure of GAP to stimulate GTP hydrolysis.
DiseaseDisease
Known diseases associated with this structure: Bladder cancer, somatic OMIM:[190020], Costello syndrome OMIM:[190020], Thyroid carcinoma, follicular, somatic OMIM:[190020]
About this StructureAbout this Structure
1AGP is a Single protein structure of sequence from Homo sapiens with and as ligands. Full crystallographic information is available from OCA.
ReferenceReference
Three-dimensional structures and properties of a transforming and a nontransforming glycine-12 mutant of p21H-ras., Franken SM, Scheidig AJ, Krengel U, Rensland H, Lautwein A, Geyer M, Scheffzek K, Goody RS, Kalbitzer HR, Pai EF, et al., Biochemistry. 1993 Aug 24;32(33):8411-20. PMID:8357792
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