The allosteric switch and conformational states in Ras GTPase affected by small molecules

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.