4NYJ

Approach for Targeting Ras with Small Molecules that Activate SOS-Mediated Nucleotide Exchange

Summary for 4NYJ

• Entry DOI: 10.2210/pdb4nyj/pdb
• Descriptor: GTPase HRas, Son of sevenless homolog 1, MAGNESIUM ION, ... (7 entities in total)
• Functional Keywords: gtpase, signaling transduction, raf, ralgds, pi3k, 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: 95023.89

Authors

Burns, M.C.,Sun, Q.,Phan, J.,Fesik, S.W. (deposition date: 2013-12-10, release date: 2014-03-12, Last modification date: 2023-09-20)

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

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: 24550516
DOI: 10.1073/pnas.1315798111

Experimental method

X-RAY DIFFRACTION (2.8522 Å)