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Updated: Apr 17, 2026

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
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Allosteric effects of the oncogenic RasQ61L mutant on Raf-RBD

Susan K Fetics1, Hugo Guterres2, Bradley M Kearney1

  • 1Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA; Department of Molecular and Structural Biochemistry, North Carolina State University, Raleigh, NC 27695, USA.

Structure (London, England : 1993)
|February 17, 2015
PubMed

Insights

The Ras/Raf/MEK/ERK pathway regulates cell proliferation. Oncogenic RasQ61L mutant constitutively activates this pathway by preventing GTP hydrolysis, with structural insights revealing long-range allosteric effects on Ras and Raf.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Structural Biology

Background:

  • The Ras/Raf/MEK/ERK pathway is crucial for cell proliferation.
  • Ras-guanosine triphosphate (GTP) activates this pathway.
  • Oncogenic RasQ61L mutant is constitutively active due to impaired GTP hydrolysis.

Purpose of the Study:

  • To elucidate the mechanism of Ras/Raf interaction and Raf kinase activation.
  • To present crystal structures of Ras-GppNHp/Raf-RBD and RasQ61L-GppNHp/Raf-RBD complexes.
  • To investigate the allosteric effects of the RasQ61L mutation.

Main Methods:

  • X-ray crystallography to determine complex structures.
  • Molecular Dynamics (MD) simulations.
  • Analysis of allosteric interactions and protein flexibility.

Main Results:

  • Crystal structures revealed differences in allosteric interactions between wild-type Ras and the RasQ61L mutant with Raf-RBD.
  • RasQ61L exhibits a rigid switch II and increased flexibility at the switch I interface.
  • Long-range effects of RasQ61L were observed on the Ras allosteric lobe and Raf-RBD.

Conclusions:

  • The RasQ61L mutation induces substantial long-range allosteric changes in Ras and Raf-RBD.
  • These findings provide mechanistic insights into Ras-driven signaling and oncogenesis.
  • Understanding these interactions may inform targeted therapeutic strategies.

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