Molecular dynamics analysis of the structures of ras-guanine nucleotide exchange protein (SOS) bound to wild-type and oncogenic ras-p21. Identification of effector domains of SOS.
The X-ray crystal structure of the ras oncogene-encoded p21 protein bound to SOS, the guanine nucleotide exchange-promoting protein, has been determined. We have undertaken to determine if there are differences between the three-dimensional structures of SOS bound to normal and oncogenic (Val 12-p21) proteins. Using molecular dynamics, we have computed the average structures for both complexes and superimposed them. We find four domains of SOS that differ markedly in structure: 631-641, 676-691, 718-729, and 994-1004. Peptides corresponding to these sequences have been synthesized and found to be powerful modulators of oncogenic p21 in cells as described in an accompanying paper. We find that the SOS segment from 809-815 makes contacts with multiple domains of ras-p21 and can facilitate correlated conformational changes in these domains.
Chen
J M
JM
Computational Chemistry Division, Wyeth-Ayerst Corporation, Pearl River, New York 10965, USA.
Friedman
F K
FK
Hyde
M J
MJ
Monaco
R
R
Pincus
M R
MR
D008958:Models, Molecular; D015689:Oncogene Protein p21(ras) / Q000737:chemistry* / Q000378:metabolism*; D011487:Protein Conformation; D020664:Son of Sevenless Proteins / Q000737:chemistry* / Q000378:metabolism*
D020664:Son of Sevenless Proteins; D015689:Oncogene Protein p21(ras)