1. Santarossa G, Roggia L, De Gioia L, Fantucci P
A Molecular Dynamics Study of the DoubleDominant Negative Mutation W809E/T935E in Ras-GEF Complex
Meeting: BITS 2004 - Year: 2004
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Abstract: Ras proteins are guanine nucleotide binding enzymes, with intrinsic low GTP-ase activity, involved in the control of cell growth and cell differentiation. They act as molecular switches, cycling between active GTPbound state and inactive GDP-bound state. Ras activation state is regulated by the competing activity of GTPase activating proteins (GAPs) and guanine nucleotide exchange factors (GEFs), the latter promoting the activation of Ras catalysing the exchange of GDP with GTP. In most tumors the activity of Ras proteins is altered, resulting in hyperactive GTP-bound forms of Ras, either because of a reduced GTPase activity or because of an increased GDP/GTP exchange. GEF mutant W809E/T935E (GEFmut) results in a dominant negative GEF, catalitically inactive, which binds to Ras with great affinity and forms a stable complex in the presence of excess nucleotide. By means of Molecular Dynamics (MD) simulations we compared different trajectories of Ras-GEFwt and Ras-GEFmut systems and analyzed them in terms of both energetic and structural parameters, to correlate the conformational differences of wt and mutant GEFs during their interaction with Ras with the observed modifications in Ras biological activity.