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Structural basis for nucleotide exchange on G alpha i subunits and receptor coupling specificity.

ABSTRACT: 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.

SUBMITTER: Johnston CA

PROVIDER: S-EPMC1794300 | biostudies-literature | 2007 Feb

REPOSITORIES: biostudies-literature

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Structural basis for nucleotide exchange on G alpha i subunits and receptor coupling specificity.

Johnston Christopher A CA Siderovski David P DP

Proceedings of the National Academy of Sciences of the United States of America 20070130 6

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 ...[more]

PMID: 17264214

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