Structural basis for nucleotide exchange on G alpha i subunits and receptor coupling specificity.
Heterotrimeric G proteins are molecular switches that relay information intracellularly in response to various extracellular signals. How ligand-activated G protein-coupled receptors act at a distance to exert exchange activity on the Galpha nucleotide binding pocket is poorly understood. Here we describe the synergistic action of two peptides: one from the third intracellular loop of the D2 dopamine receptor (D2N), and a second, Galpha.GDP-binding peptide (KB-752) that mimics the proposed role of Gbetagamma in receptor-promoted nucleotide exchange. The structure of both peptides in complex with Galpha(i1) suggests that conformational changes in the beta3/alpha2 loop and beta6 strand act in concert for efficient nucleotide exchange. Two key residues in the alpha4 helix were found to define a receptor/Galpha(i) coupling specificity determinant.
Johnston
Christopher A
CA
Department of Pharmacology and UNC Neuroscience Center, School of Medicine, University of North Carolina, Chapel Hill, NC 27599-7365, USA.
Siderovski
David P
DP
D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D009711:Nucleotides / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*
D009711:Nucleotides; D043562:Receptors, G-Protein-Coupled; D019206:GTP-Binding Protein alpha Subunits, Gi-Go