Download MendeleyStructural determinants for regulation of phosphodiesterase by a G protein at 2.0 A.
Slep, K.C., Kercher, M.A., He, W., Cowan, C.W., Wensel, T.G., Sigler, P.B.(2001) Nature 409: 1071-1077
- PubMed: 11234020
- DOI: https://doi.org/10.1038/35059138
- Primary Citation of Related Structures:
1FQI, 1FQJ, 1FQK - PubMed Abstract:
A multitude of heptahelical receptors use heterotrimeric G proteins to transduce signals to specific effector target molecules. The G protein transducin, Gt, couples photon-activated rhodopsin with the effector cyclic GMP phosophodiesterase (PDE) in the vertebrate phototransduction cascade. The interactions of the Gt alpha-subunit (alpha(t)) with the inhibitory PDE gamma-subunit (PDEgamma) are central to effector activation, and also enhance visual recovery in cooperation with the GTPase-activating protein regulator of G-protein signalling (RGS)-9 (refs 1-3). Here we describe the crystal structure at 2.0 A of rod transducin alpha x GDP x AlF4- in complex with the effector molecule PDEgamma and the GTPase-activating protein RGS9. In addition, we present the independently solved crystal structures of the RGS9 RGS domain both alone and in complex with alpha(t/i1) x GDP x AlF4-. These structures reveal insights into effector activation, synergistic GTPase acceleration, RGS9 specificity and RGS activity. Effector binding to a nucleotide-dependent site on alpha(t) sequesters PDEgamma residues implicated in PDE inhibition, and potentiates recruitment of RGS9 for hydrolytic transition state stabilization and concomitant signal termination.
Organizational Affiliation:
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06511, USA. [email protected]
