Structural differences between a ras oncogene protein and the normal protein

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Abstract
One of the most commonly found transforming ras oncogenes in human tumours has a valine codon replacing the glycine codon at position 12 of the normal c-Ha-ras gene1–4. To understand the structural reasons behind cell transformation arising from this single amino acid substitution, we have determined the crystal structure of the GDP-bound form of the mutant protein, p21(Val-12), encoded by this oncogene. We report here the overall structure of p21(Val-12) at 2.2 Å resolution and compare it with the structure of the normal c-Ha-ras protein5. One of the major differences is that the loop of the transforming ras protein that binds the β-phosphate of the guanine nucleotide is enlarged. Such a change in the "catalytic site' conformation could explain the reduced GTPase activity of the mutant6–8, which keeps the protein in the GTP bound 'signal on9 state for a prolonged period of time, ultimately causing cell transformation.