We have used heteronuclear three-dimensional NMR spectroscopy to determine the solution structure of a 141 residue protein containing the GTPase activating domain from the alpha chain of the heterotrimeric G protein Gs. The domain contains six alpha-helices and is stable and structured in solution despite having been excised from the intact Gs protein. The N-terminal ten and C-terminal 11 residues of the protein are unstructured in solution while the core is well determined by the 2483 distance and torsion restraints derived from the NMR spectra. The final ensemble of 14 structures, generated with a hybrid distance geometry/simulated annealing protocol, have an average to-the-mean backbone root-mean-square deviation of 0.39 A for the core residues 89 to 201. The majority of the structure is remarkably similar to that observed for the cognate domains in crystal structures of the homologous proteins alpha t and alpha i1. However, the orientations of the second helix and the subsequent interhelical loops differ markedly among the three proteins. This structural divergence, along with functional studies of chimeric proteins, suggests that this region of the domain interacts with either the downstream effector adenylyl cyclase or with some other intermediary protein.