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Nat Commun. 2017 Dec 18;8(1):2169. doi: 10.1038/s41467-017-02257-x.

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

Author information

1
Department of Biochemistry, Institute for Research in Immunology and Cancer, Université de Montreal, Montreal, QC, Canada.
2
Department of Structural and Computational Biology and Molecular Biophysics, Baylor College of Medicine, Houston, TX, USA.
3
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
4
Institute of Pharmacology and Toxicology, Würzburg, Germany.
5
Max Delbrück Center for Molecular Medicine, Berlin, Germany.
6
Departments of Statistics and Bioengineering, Rice University, Houston, TX, USA.
7
Department of Biochemistry, Institute for Research in Immunology and Cancer, Université de Montreal, Montreal, QC, Canada. michel.bouvier@umontreal.ca.

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. 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.

PMID:
29255305
PMCID:
PMC5735088
DOI:
10.1038/s41467-017-02257-x
[Indexed for MEDLINE]
Free PMC Article

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