title: The allosteric switch and conformational states in Ras GTPase affected by small molecules.
abstract: Ras is a hub protein in signal transduction pathways leading to the control of cell proliferation, migration, and survival and a major target for drug discovery due to the presence of its mutants in about 20% of human cancers. Yet, the discovery of small molecules that can directly interfere with its function has been elusive in spite of intense efforts. This is most likely due to its highly flexible nature and the lack of a well-ordered active site. This chapter contains a discussion of our current understanding of conformational states in Ras-GTP, with focus on a recently discovered allosteric switch mechanism that may promote intrinsic hydrolysis of GTP in the presence of Raf. We discuss the manner in which small molecules are known to affect the equilibrium of states in Ras-GTP and suggest novel strategies to go forward in the search for inhibitors of this master signaling protein.
authors.affiliation: Department of Chemistry and Chemical Biology, Northeastern University, 360 Huntington Ave, Boston, Massachusetts, USA.
authors.forename: Christian W
authors.initials: CW
authors.lastname: Johnson
authors.affiliation: Department of Chemistry and Chemical Biology, Northeastern University, 360 Huntington Ave, Boston, Massachusetts, USA. Electronic address: c.mattos@neu.edu.
authors.forename: Carla
authors.initials: C
authors.lastname: Mattos
mesh_terms: D000495:Allosteric Site; D000818:Animals; D006801:Humans; D004364:Pharmaceutical Preparations; D011487:Protein Conformation; D054852:Small Molecule Libraries; D020703:ras GTPase-Activating Proteins / Q000737:chemistry* / Q000378:metabolism
chemical_list: D004364:Pharmaceutical Preparations; D054852:Small Molecule Libraries; D020703:ras GTPase-Activating Proteins
keywords: Allosteric modulation; Allosteric networks; Binding site hot spots; FTMap; G domain; GTPase; MSCS; Oncogenic mutants; Protein conformation; Raf; Ras; Ras inhibitor; Ras intrinsic hydrolysis; Ras/Raf/MEK/ERK pathway