The Protein Journal

, Volume 24, Issue 6, pp 391–398 | Cite as

Comparison of the Predicted Structures of Loops in the ras–SOS Protein Bound to a Single ras-p21 Protein with the Crystallographically Determined Structures in SOS Bound to Two ras-p21 Proteins



We have previously computed the structures of three loops, residues 591–596, 654–675 and 742–751, in the ras-p21 protein-binding domain (residues 568–1044) of the guanine nucleotide-exchange-promoting SOS protein that were crystallographically undefined when one molecule of ras-p21 (unbound to nucleotide) binds to SOS. Based on our computational results, we synthesized three peptides corresponding to sequences of each of these three loops and found that all three peptides strongly inhibit ras-p21 signaling. More recently, a new crystal structure of SOS has been determined in which this protein binds to two molecules of ras-p21, one unbound to GTP and one bound to GTP. In this structure, the 654–675 loop and residues 742–743 and 750–751 are now crystallographically defined. We have superimposed our energy-minimized structure of the ras-binding domain of SOS bound to one molecule of ras-p21 on the X-ray structure for SOS bound to two molecules of ras-p21. We find that, while the two structures are superimposable, there are large deviations of the residues 673 and 676 and 741 and 752, flanking the two loop segments. This suggests that the binding of the extra ras-p21 molecule, which is far from each of the three loops, induces conformational changes in these domains and further supports their role in signal transduction. In spite of these differences, we have superimposed our computed structures for the loop residues on those from the more recent X-ray structure. Our structure for the 654–675 segment is an anti-parallel beta-sheet with a reverse turn at residues 663–665; in the X-ray structure residues 655–662 adopt an alpha-helical conformation; on the other hand, our computed structure for residues 663–675 superimpose on the X-ray structure for these residues. We further find that our computed structures for residues 742–743 and 750–751 are superimposable on the X-ray structure for these residues.


Computed structures crystallographically undefined loops oncogenic ras-p21 SOS X-ray structure 



GTPase activating protein


guanosine triphosphate


ras-exchanger motif (second ras-p21 binding site in SOS)


root mean square


guanine nucleotide exchange-promoting protein, also referred to as “son-of-sevenless” (SOS) in Drosophila.


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  1. Birchmeier, C., Broek, D., Wigler, M. 1985Cell43615621CrossRefGoogle Scholar
  2. Boriak-Sjodin, P. A., Margarit, S. M., Bar-Sagi, D., Kuriyan, J. 1998Nature394337343(London)Google Scholar
  3. Chen, J. M., Friedman, F. K., Hyde, M. J., Monaco, R., Pincus, M. R. 1999J. Protein Chem.18867874Google Scholar
  4. Chie, L., Chen, J. M., Friedman, F. K., Chung, D. L., Amar, S., Michl, J., Yamiazumi, Z., Pincus, M. R. 1999J. Protein Chem.18875879Google Scholar
  5. Chie, L., Friedman, F. K., Duncan, T., Chen, J. M., Chung, D. L., Pincus, M. R. 2004Protein J.23229234Google Scholar
  6. Chie, L., Chung, D., and Pincus, M. R. (2005). Protein J. (in press)Google Scholar
  7. Crennell, S., Garman, E., Laver, G., Vimr, E., Taylor, G. 1994Structure2535544CrossRefGoogle Scholar
  8. Deshpande, A. K., Kung, H.-F. 1987Mol. Cell. Biol.712851288Google Scholar
  9. Duncan, T., Chen, J. M., Friedman, F. K., Hyde, M., Pincus, M. R. 2004Protein J.23217228CrossRefGoogle Scholar
  10. Margarit, S. M., Sondermann, H., Hall, B. E., Nagar, B., Hoelz, A., Pirruccello, M., Bar-Sagi, D., Kuriyan,  2003Cell112685695CrossRefGoogle Scholar
  11. Pincus, M. R., Brandt-Rauf, P. W., Michl, J., Friedman, F. K. 2000Cancer Invest.183950Google Scholar
  12. Pincus, M. R. 2004Front. Biosci.934863509Google Scholar

Copyright information

© Springer Science+Business Media, Inc. 2005

Authors and Affiliations

  1. 1.Department of PathologyNew York Harbor VA Medical CenterBrooklyn
  2. 2.Department of PathologySUNY Downstate Medical CenterBrooklyn
  3. 3.Advanced Computer ServicesDewitt

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