Mapping the nucleotide and isoform-dependent structural and dynamical features of Ras proteins

Structure. 2008 Jun;16(6):885-96. doi: 10.1016/j.str.2008.03.009.


Ras GTPases are conformational switches controlling cell proliferation, differentiation, and development. Despite their prominent role in many forms of cancer, the mechanism of conformational transition between inactive GDP-bound and active GTP-bound states remains unclear. Here we describe a detailed analysis of available experimental structures and molecular dynamics simulations to quantitatively assess the structural and dynamical features of active and inactive states and their interconversion. We demonstrate that GTP-bound and nucleotide-free G12V H-ras sample a wide region of conformational space, and show that the inactive-to-active transition is a multiphase process defined by the relative rearrangement of the two switches and the orientation of Tyr32. We also modeled and simulated N- and K-ras proteins and found that K-ras is more flexible than N- and H-ras. We identified a number of isoform-specific, long-range side chain interactions that define unique pathways of communication between the nucleotide binding site and the C terminus.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Catalytic Domain
  • Computer Simulation
  • Guanosine Diphosphate / chemistry
  • Guanosine Triphosphate / chemistry
  • Models, Molecular
  • Molecular Sequence Data
  • Protein Conformation
  • Protein Isoforms / chemistry
  • ras Proteins / chemistry*


  • Protein Isoforms
  • Guanosine Diphosphate
  • Guanosine Triphosphate
  • ras Proteins