STRUCTURAL EFFECTS OF THE BINDING OF GTP TO THE WILD-TYPE AND ONCOGENIC FORMS OF THE RAS-GENE-ENCODED P21 PROTEINS

Molecular dynamics calculations have been performed to determine the a verage structures of ras-gene-encoded p21 proteins bound to GTP, i.e., the normal (wild-type) protein and two oncogenic forms of this protei n, the Val 12- and Leu 61-p21 proteins. We find that the average struc tures for all of these proteins exhibit low coordinate fluctuations (w hich are highest for the normal protein), indicating convergence to sp ecific structures. From previous dynamics calculations of the average structures of these proteins bound to GDP, major regional differences were found among these proteins [Monaco et nl. (1995), J. Protein Chem ., in press]. We now find that the average structures of the oncogenic proteins are more similar to one another when the proteins are bound to GTP than when they are bound to GDP [Monaco er al. (1995), J. Prote in Chem., in press]. However, they still differ in structure at specif ic amino acid residues rather than in whole regions, in contradistinct ion to the results found for the p21-GDP complexes. Two exceptions are the regions 25-32, in an cu-helical region, and 97-110. The two oncog enic (Val 12- and Leu 61-) proteins have similar structures which diff er significantly in the region of residues 97-110. This region has rec ently been identified as being critical in the interaction of p21 with kinase target proteins. The differences in structure between the onco genic proteins suggest the existence of more than one oncogenic form o f the p21 protein that can activate different signaling pathways.