Structural and functional analysis of the regulator of G protein signaling 2-gαq complex

Structure. 2013 Mar 5;21(3):438-48. doi: 10.1016/j.str.2012.12.016. Epub 2013 Feb 21.


The heterotrimeric G protein Gαq is a key regulator of blood pressure, and excess Gαq signaling leads to hypertension. A specific inhibitor of Gαq is the GTPase activating protein (GAP) known as regulator of G protein signaling 2 (RGS2). The molecular basis for how Gαq/11 subunits serve as substrates for RGS proteins and how RGS2 mandates its selectivity for Gαq is poorly understood. In crystal structures of the RGS2-Gαq complex, RGS2 docks to Gαq in a different orientation from that observed in RGS-Gαi/o complexes. Despite its unique pose, RGS2 maintains canonical interactions with the switch regions of Gαq in part because its α6 helix adopts a distinct conformation. We show that RGS2 forms extensive interactions with the α-helical domain of Gαq that contribute to binding affinity and GAP potency. RGS subfamilies that do not serve as GAPs for Gαq are unlikely to form analogous stabilizing interactions.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Cattle
  • Crystallography, X-Ray
  • Escherichia coli / genetics
  • GTP-Binding Protein alpha Subunits, Gq-G11 / chemistry*
  • GTP-Binding Protein alpha Subunits, Gq-G11 / genetics
  • Humans
  • Mice
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation*
  • Molecular Sequence Data
  • Mutation
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Protein Structure, Secondary
  • Protein Subunits / chemistry*
  • Protein Subunits / genetics
  • RGS Proteins / chemistry*
  • RGS Proteins / genetics
  • Rats
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Sequence Alignment
  • Structure-Activity Relationship


  • Protein Subunits
  • RGS Proteins
  • RGS2 protein, human
  • Recombinant Proteins
  • GTP-Binding Protein alpha Subunits, Gq-G11

Associated data

  • PDB/4EKC
  • PDB/4EKD