Structural determinants for GoLoco-induced inhibition of nucleotide release by Galpha subunits

Nature. 2002 Apr 25;416(6883):878-81. doi: 10.1038/416878a.


Heterotrimeric G-proteins bind to cell-surface receptors and are integral in transmission of signals from outside the cell. Upon activation of the Galpha subunit by binding of GTP, the Galpha and Gbetagamma subunits dissociate and interact with effector proteins for signal transduction. Regulatory proteins with the 19-amino-acid GoLoco motif can bind to Galpha subunits and maintain G-protein subunit dissociation in the absence of Galpha activation. Here we describe the structural determinants of GoLoco activity as revealed by the crystal structure of Galpha(i1) GDP bound to the GoLoco region of the 'regulator of G-protein signalling' protein RGS14. Key contacts are described between the GoLoco motif and Galpha protein, including the extension of GoLoco's highly conserved Asp/Glu-Gln-Arg triad into the nucleotide-binding pocket of Galpha to make direct contact with the GDP alpha- and beta-phosphates. The structural organization of the GoLoco Galpha(i1) complex, when combined with supporting data from domain-swapping experiments, suggests that the Galpha all-helical domain and GoLoco-region carboxy-terminal residues control the specificity of GoLoco Galpha interactions.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Crystallography, X-Ray
  • Guanosine Triphosphate / metabolism*
  • Heterotrimeric GTP-Binding Proteins / antagonists & inhibitors*
  • Heterotrimeric GTP-Binding Proteins / chemistry
  • Heterotrimeric GTP-Binding Proteins / metabolism*
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Peptide Fragments / chemistry
  • Peptide Fragments / metabolism
  • Protein Binding
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Protein Subunits
  • RGS Proteins / chemistry*
  • RGS Proteins / metabolism*
  • Rats
  • Sequence Alignment
  • Structure-Activity Relationship


  • Peptide Fragments
  • Protein Subunits
  • RGS Proteins
  • RGS14 protein, human
  • Rgs14 protein, rat
  • Guanosine Triphosphate
  • Heterotrimeric GTP-Binding Proteins

Associated data

  • PDB/1KJY