Intramolecular allosteric communication in dopamine D2 receptor revealed by evolutionary amino acid covariation.

ABSTRACT: The structural basis of allosteric signaling in G protein-coupled receptors (GPCRs) is important in guiding design of therapeutics and understanding phenotypic consequences of genetic variation. The Evolutionary Trace (ET) algorithm previously proved effective in redesigning receptors to mimic the ligand specificities of functionally distinct homologs. We now expand ET to consider mutual information, with validation in GPCR structure and dopamine D2 receptor (D2R) function. The new algorithm, called ET-MIp, identifies evolutionarily relevant patterns of amino acid covariations. The improved predictions of structural proximity and D2R mutagenesis demonstrate that ET-MIp predicts functional interactions between residue pairs, particularly potency and efficacy of activation by dopamine. Remar

SUBMITTER: Sung YM 

PROVIDER: S-EPMC4822589 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature