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Nat Commun. 2019 Feb 8;10(1):667. doi: 10.1038/s41467-019-08630-2.

A conserved molecular switch in Class F receptors regulates receptor activation and pathway selection.

Author information

1
Section of Receptor Biology & Signaling, Dept. Physiology & Pharmacology, Karolinska Institutet, S17165, Stockholm, Sweden.
2
MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge, CB2 0QH, United Kingdom.
3
Science for Life Laboratory, Department of Cell and Molecular Biology, Uppsala University, P.O. Box 596, SE-751 24, Uppsala, Sweden.
4
Department of Pharmacology and Toxicology, Medical College of Georgia at Augusta University, Augusta, Georgia, 30912, USA.
5
Section of Receptor Biology & Signaling, Dept. Physiology & Pharmacology, Karolinska Institutet, S17165, Stockholm, Sweden. gunnar.schulte@ki.se.

Abstract

Class F receptors are considered valuable therapeutic targets due to their role in human disease, but structural changes accompanying receptor activation remain unexplored. Employing population and cancer genomics data, structural analyses, molecular dynamics simulations, resonance energy transfer-based approaches and mutagenesis, we identify a conserved basic amino acid in TM6 in Class F receptors that acts as a molecular switch to mediate receptor activation. Across all tested Class F receptors (FZD4,5,6,7, SMO), mutation of the molecular switch confers an increased potency of agonists by stabilizing an active conformation as assessed by engineered mini G proteins as conformational sensors. Disruption of the switch abrogates the functional interaction between FZDs and the phosphoprotein Dishevelled, supporting conformational selection as a prerequisite for functional selectivity. Our studies reveal the molecular basis of a common activation mechanism conserved in all Class F receptors, which facilitates assay development and future discovery of Class F receptor-targeting drugs.

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