title: Small-molecule ligands bind to a distinct pocket in Ras and inhibit SOS-mediated nucleotide exchange activity.
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.
authors.affiliation: Structural Biology, Genentech, Inc., One DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Till
authors.initials: T
authors.lastname: Maurer
authors.forename: Lindsay S
authors.initials: LS
authors.lastname: Garrenton
authors.forename: Angela
authors.initials: A
authors.lastname: Oh
authors.forename: Keith
authors.initials: K
authors.lastname: Pitts
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Anderson
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Skelton
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Fauber
authors.forename: Borlan
authors.initials: B
authors.lastname: Pan
authors.forename: Shiva
authors.initials: S
authors.lastname: Malek
authors.forename: David
authors.initials: D
authors.lastname: Stokoe
authors.forename: Mary J C
authors.initials: MJ
authors.lastname: Ludlam
authors.forename: Krista K
authors.initials: KK
authors.lastname: Bowman
authors.forename: Jiansheng
authors.initials: J
authors.lastname: Wu
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Giannetti
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Starovasnik
authors.forename: Ira
authors.initials: I
authors.lastname: Mellman
authors.forename: Peter K
authors.initials: PK
authors.lastname: Jackson
authors.forename: Joachim
authors.initials: J
authors.lastname: Rudolph
authors.forename: Weiru
authors.initials: W
authors.lastname: Wang
authors.forename: Guowei
authors.initials: G
authors.lastname: Fang
mesh_terms: D001665:Binding Sites; D002460:Cell Line; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D009711:Nucleotides / Q000378:metabolism*; D020664:Son of Sevenless Proteins / Q000378:metabolism*; D018631:ras Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D008024:Ligands; D009711:Nucleotides; D020664:Son of Sevenless Proteins; D018631:ras Proteins