Identification, using molecular dynamics, of an effector domain of the ras-binding domain of the raf-p74 protein that is uniquely involved in oncogenic ras-p21 signaling.
By comparing the average structures, computed using molecular dynamics, of the ras-binding domain of raf (RBD) bound to activated wild-type ras-p21 and its homologous inhibitory protein, rap-1A, we formerly identified three domains of the RBD that changed conformation between the two complexes, residues 62-76, 97-110, and 111-121. We found that one synthetic peptide, corresponding to RBD residues 97-110, selectively inhibited oncogenic ras-p21-induced oocyte maturation. In this study, we performed molecular dynamics on the Val 12-ras-p21-RBD complex and compared its average structure with that for the wild-type protein. We find that there is a large displacement of a loop involving these residues when the structures of the two complexes are compared. This result corroborates our former finding that the RBD 97-110 peptide inhibits only signal transduction by oncogenic ras-p21 and suggests that oncogenic p21 uses this loop to interact with raf in a unique manner.
Tularik, Inc, South San Francisco, California 94080, USA.
J M
JM
Chen
K
K
Rijhwani
F K
FK
Friedman
M J
MJ
Hyde
M R
MR
Pincus
D019943:Amino Acid Substitution; D001665:Binding Sites; D006801:Humans; D008958:Models, Molecular; D017711:Nonlinear Dynamics; D015689:Oncogene Protein p21(ras) / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D019908:Proto-Oncogene Proteins c-raf / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D016283:Proto-Oncogene Proteins p21(ras) / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020827:rap1 GTP-Binding Proteins / Q000737:chemistry / Q000378:metabolism
D010446:Peptide Fragments; D019908:Proto-Oncogene Proteins c-raf; C501009:HRAS protein, human; D015689:Oncogene Protein p21(ras); D016283:Proto-Oncogene Proteins p21(ras); D020827:rap1 GTP-Binding Proteins