TY  - JOUR
A1  - Schönegge, Anne-Marie
A1  - Gallion, Jonathan
A1  - Picard, Louis-Philippe
A1  - Wilkins, Angela D.
A1  - Le Gouill, Christian
A1  - Audet, Martin
A1  - Stallaert, Wayne
A1  - Lohse, Martin J.
A1  - Kimmel, Marek
A1  - Lichtarge, Olivier
A1  - Bouvier, Michel
T1  - Evolutionary action and structural basis of the allosteric switch controlling β\(_2\)AR functional selectivity
JF  - Nature Communications
N2  - 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 β\(_2\)-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. Robustness of the results is confirmed using simulation-based error propagation. The structural changes resulting from functionally biasing mutations centered around the DRY, NPxxY, and PIF motifs, selectively linking these micro-switches to unique signaling profiles. Our data identify different receptor regions that are important for the stabilization of distinct conformations underlying functional selectivity.
KW  - toxicology
KW  - functional clustering
KW  - molecular modelling
KW  - protein design
KW  - receptor pharmacology
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-172268
VL  - 8
ER  -