Evolutionary action and structural basis of the allosteric switch controlling β₂AR functional selectivity.

ABSTRACT: Functional selectivity of G-protein-coupled receptors is believed to originate from ligand-specific conformations that activate only subsets of signaling effectors. In this study, to identify molecular motifs playing important roles in transducing ligand binding into distinct signaling responses, we combined in silico evolutionary lineage analysis and structure-guided site-directed mutagenesis with large-scale functional signaling characterization and non-negative matrix factorization clustering of signaling profiles. Clustering based on the signaling profiles of 28 variants of the β₂-adrenergic receptor reveals three clearly distinct phenotypical clusters, showing selective impairments of either the Gi or βarrestin/endocytosis pathways with no effect on Gs activation. Robustnes

SUBMITTER: Schonegge AM 

PROVIDER: S-EPMC5735088 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature