4NYI
Approach for Targeting Ras with Small Molecules that Activate SOS-Mediated Nucleotide Exchange
Summary for 4NYI
| Entry DOI | 10.2210/pdb4nyi/pdb |
| Descriptor | GTPase HRas, Son of sevenless homolog 1, MAGNESIUM ION, ... (7 entities in total) |
| Functional Keywords | ras sos complex, signal transduction, raf, pi3k, poly-petide, cytosol, signaling protein |
| Biological source | Homo sapiens (human) More |
| Cellular location | Cell membrane. Isoform 2: Nucleus: P01112 P01112 |
| Total number of polymer chains | 3 |
| Total formula weight | 95281.18 |
| Authors | Burns, M.C.,Sun, Q.,Phan, J.,Fesik, S.W. (deposition date: 2013-12-10, release date: 2014-03-12, Last modification date: 2024-02-28) |
| Primary citation | Burns, M.C.,Sun, Q.,Daniels, R.N.,Camper, D.,Kennedy, J.P.,Phan, J.,Olejniczak, E.T.,Lee, T.,Waterson, A.G.,Rossanese, O.W.,Fesik, S.W. Approach for targeting Ras with small molecules that activate SOS-mediated nucleotide exchange. Proc.Natl.Acad.Sci.USA, 111:3401-3406, 2014 Cited by PubMed Abstract: Aberrant activation of the small GTPase Ras by oncogenic mutation or constitutively active upstream receptor tyrosine kinases results in the deregulation of cellular signals governing growth and survival in ∼30% of all human cancers. However, the discovery of potent inhibitors of Ras has been difficult to achieve. Here, we report the identification of small molecules that bind to a unique pocket on the Ras:Son of Sevenless (SOS):Ras complex, increase the rate of SOS-catalyzed nucleotide exchange in vitro, and modulate Ras signaling pathways in cells. X-ray crystallography of Ras:SOS:Ras in complex with these molecules reveals that the compounds bind in a hydrophobic pocket in the CDC25 domain of SOS adjacent to the Switch II region of Ras. The structure-activity relationships exhibited by these compounds can be rationalized on the basis of multiple X-ray cocrystal structures. Mutational analyses confirmed the functional relevance of this binding site and showed it to be essential for compound activity. These molecules increase Ras-GTP levels and disrupt MAPK and PI3K signaling in cells at low micromolar concentrations. These small molecules represent tools to study the acute activation of Ras and highlight a pocket on SOS that may be exploited to modulate Ras signaling. PubMed: 24550516DOI: 10.1073/pnas.1315798111 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.9612 Å) |
Structure validation
Download full validation report
