4DSN

Small-molecule ligands bind to a distinct pocket in Ras and inhibit SOS-mediated nucleotide exchange activity

Summary for 4DSN

• Entry DOI: 10.2210/pdb4dsn/pdb
• Related: 4DSO 4DST 4DSU
• Descriptor: GTPase KRas, isoform 2B, PHOSPHOMETHYLPHOSPHONIC ACID GUANYLATE ESTER, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: small g-protein, signaling, hydrolase
• Biological source: Homo sapiens (human)
• Cellular location: Cell membrane; Lipid-anchor; Cytoplasmic side: P01116
• Total number of polymer chains: 1
• Total formula weight: 22224.53

Authors

Oh, A.,Maurer, T.,Garrenton, L.S.,Pitts, K.,Anderson, D.J.,Skelton, N.J.,Fauber, B.P.,Pan, B.,Malek, S.,Stokoe, D.,Ludlam, M.,Bowman, K.K.,Wu, J.,Giannetti, A.M.,Starovasnik, M.A.,Mellman, I.,Jackson, P.K.,Ruldolph, J.,Fang, G.,Wang, W. (deposition date: 2012-02-19, release date: 2012-04-25, Last modification date: 2024-02-28)

Primary citation

Maurer, T.,Garrenton, L.S.,Oh, A.,Pitts, K.,Anderson, D.J.,Skelton, N.J.,Fauber, B.P.,Pan, B.,Malek, S.,Stokoe, D.,Ludlam, M.J.,Bowman, K.K.,Wu, J.,Giannetti, A.M.,Starovasnik, M.A.,Mellman, I.,Jackson, P.K.,Rudolph, J.,Wang, W.,Fang, G.
Small-molecule ligands bind to a distinct pocket in Ras and inhibit SOS-mediated nucleotide exchange activity.
Proc.Natl.Acad.Sci.USA, 109:5299-5304, 2012

PubMed Abstract: The Ras gene is frequently mutated in cancer, and mutant Ras drives tumorigenesis. Although Ras is a central oncogene, small molecules that bind to Ras in a well-defined manner and exert inhibitory effects have not been uncovered to date. Through an NMR-based fragment screen, we identified a group of small molecules that all bind to a common site on Ras. High-resolution cocrystal structures delineated a unique ligand-binding pocket on the Ras protein that is adjacent to the switch I/II regions and can be expanded upon compound binding. Structure analysis predicts that compound-binding interferes with the Ras/SOS interactions. Indeed, selected compounds inhibit SOS-mediated nucleotide exchange and prevent Ras activation by blocking the formation of intermediates of the exchange reaction. The discovery of a small-molecule binding pocket on Ras with functional significance provides a new direction in the search of therapeutically effective inhibitors of the Ras oncoprotein.

PubMed: 22431598
DOI: 10.1073/pnas.1116510109

Experimental method

X-RAY DIFFRACTION (2.03 Å)