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. 2010 Dec 1;99(11):L87-9.
doi: 10.1016/j.bpj.2010.10.020.

Conformational Selection in G-proteins: Lessons From Ras and Rho

Free PMC article

Conformational Selection in G-proteins: Lessons From Ras and Rho

Barry J Grant et al. Biophys J. .
Free PMC article

Abstract

The induced fit model has traditionally been invoked to describe the activating conformational change of the monomeric G-proteins, such as Ras and Rho. With this scheme, the presence or absence of the γ-phosphate of GTP leads to an instantaneous switch in conformation. Here we describe atomistic molecular simulations that demonstrate that both Ras and Rho superfamily members harbor an intrinsic susceptibility to sample multiple conformational states in the absence of nucleotide ligand. By comparing the distribution of conformers in the presence and absence of nucleotide, we show that conformational selection is the dominant mechanism by which Ras and Rho undergo nucleotide-dependent conformational changes. Furthermore, the pattern of correlated motions revealed by these simulations predicts a preserved allosteric coupling of the nucleotide-binding site with the membrane interacting C-terminus in both Rho and Ras.

Figures

Figure 1
Figure 1
Ras (AC) and Rho (DF) conformations from crystallography and simulation. Crystallographic GTP conformers are colored red, GDP green, and nucleotide free conformers gray. The distribution of MD conformers is depicted with density-shaded blue points from (A) Ras nucleotide free, (B) Ras GTP-bound, (C) Ras GDP-bound, (D) Rho nucleotide free, (E) Rho GTP-bound, and (F) Rho GDP-bound simulations.
Figure 2
Figure 2
Wild-type and mutant simulations suggest that loop 3 (L3) is a potential allosteric site. (A) Correlated motions during wild-type Ras (upper triangle) and Rho (lower triangle) simulations. Correlations with L3-S1-S2 are highlighted with dashed green ovals. (B) Simulations with L3 D47A/E49A mutants (blue lines) display increased flexibility of SI and L3 over wild-type simulations (black lines). α5 R161A/R164A mutants (orange lines) are also shown. Dashed lines represent replicate simulations, two for each system (see the Supporting Material for details).

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