Crystal structure of the GTPase-activating domain of human p120GAP and implications for the interaction with Ras

Nature. 1996 Dec 12;384(6609):591-6. doi: 10.1038/384591a0.


Ras-related GTP-binding proteins function as molecular switches which cycle between GTP-bound 'on'- and GDP-bound 'off'-states. GTP hydrolysis is the common timing mechanism that mediates the return from the 'on' to the 'off'-state. It is usually slow but can be accelerated by orders of magnitude upon interaction with GTPase-activating proteins (GAPs). In the case of Ras, a major regulator of cellular growth, point mutations are found in approximately 30% of human tumours which render the protein unable to hydrolyse GTP, even in the presence of Ras-GAPs. The first structure determination of a GTPase-activating protein reveals the catalytically active fragment of the Ras-specific p120GAP (ref. 2), GAP-334, as an elongated, exclusively helical protein which appears to represent a novel protein fold. The molecule consists of two domains, one of which contains all the residues conserved among different GAPs for Ras. From the location of conserved residues around a shallow groove in the central domain we can identify the site of interaction with Ras x GTP. This leads to a model for the interaction between Ras and GAP that satisfies numerous biochemical and genetic data on this important regulatory process.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Catalysis
  • Crystallography, X-Ray
  • GTP Phosphohydrolases / metabolism
  • GTPase-Activating Proteins
  • Guanosine Triphosphate / metabolism
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation
  • Peptide Fragments / chemistry*
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism
  • Protein Conformation*
  • Protein Folding
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Proteins / chemistry*
  • Proteins / genetics
  • Proteins / metabolism
  • Recombinant Proteins / chemistry
  • ras GTPase-Activating Proteins
  • ras Proteins / metabolism*


  • GTPase-Activating Proteins
  • Peptide Fragments
  • Proteins
  • Recombinant Proteins
  • ras GTPase-Activating Proteins
  • Guanosine Triphosphate
  • GTP Phosphohydrolases
  • ras Proteins

Associated data

  • GENBANK/M23379
  • PDB/1WER