Crystal structure of a small G protein in complex with the GTPase-activating protein rhoGAP

Nature. 1997 Aug 14;388(6643):693-7. doi: 10.1038/41805.


Small G proteins transduce signals from plasma-membrane receptors to control a wide range of cellular functions. These proteins are clustered into distinct families but all act as molecular switches, active in their GTP-bound form but inactive when GDP-bound. The Rho family of G proteins, which includes Cdc42Hs, activate effectors involved in the regulation of cytoskeleton formation, cell proliferation and the JNK signalling pathway. G proteins generally have a low intrinsic GTPase hydrolytic activity but there are family-specific groups of GTPase-activating proteins (GAPs) that enhance the rate of GTP hydrolysis by up to 10(5) times. We report here the crystal structure of Cdc42Hs, with the non-hydrolysable GTP analogue GMPPNP, in complex with the GAP domain of p50rhoGAP at 2.7A resolution. In the complex Cdc42Hs interacts, mainly through its switch I and II regions, with a shallow pocket on rhoGAP which is lined with conserved residues. Arg 85 of rhoGAP interacts with the P-loop of Cdc42Hs, but from biochemical data and by analogy with the G-protein subunit G(i alpha1), we propose that it adopts a different conformation during the catalytic cycle which enables it to stabilize the transition state of the GTP-hydrolysis reaction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arginine / chemistry
  • Cell Cycle Proteins / chemistry*
  • Crystallography, X-Ray
  • Enzyme Activation
  • GTP Phosphohydrolases / metabolism
  • GTP-Binding Proteins / chemistry*
  • GTPase-Activating Proteins*
  • Guanosine Triphosphate / analogs & derivatives
  • Guanosine Triphosphate / chemistry
  • Models, Molecular
  • Protein Conformation
  • cdc42 GTP-Binding Protein


  • Cell Cycle Proteins
  • GTPase-Activating Proteins
  • rho GTPase-activating protein
  • Guanosine Triphosphate
  • Arginine
  • GTP Phosphohydrolases
  • GTP-Binding Proteins
  • cdc42 GTP-Binding Protein

Associated data

  • PDB/1AM4