%0 Journal Article %1 pmid30737406 %A Wright, S. C. %A Kozielewicz, P. %A Kowalski-Jahn, M. %A Petersen, J. %A Bowin, C. F. %A Slodkowicz, G. %A Marti-Solano, M. %A Rodr?guez, D. %A Hot, B. %A Okashah, N. %A Strakova, K. %A Valnohova, J. %A Babu, M. M. %A Lambert, N. A. %A Carlsson, J. %A Schulte, G. %D 2019 %J Nat Commun %K imported %N 1 %P 667 %T A conserved molecular switch in Class F receptors regulates receptor activation and pathway selection %V 10 %X 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.

@article{pmid30737406, 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.}, added-at = {2021-01-14T21:21:20.000+0100}, author = {Wright, S. C. and Kozielewicz, P. and Kowalski-Jahn, M. and Petersen, J. and Bowin, C. F. and Slodkowicz, G. and Marti-Solano, M. and Rodr?guez, D. and Hot, B. and Okashah, N. and Strakova, K. and Valnohova, J. and Babu, M. M. and Lambert, N. A. and Carlsson, J. and Schulte, G.}, biburl = {https://www.bibsonomy.org/bibtex/2cae89a4d9c871614f5b88eeecbd744d7/mbgroup}, interhash = {bd9c4d3f857c187d91094e1ea0f1f545}, intrahash = {cae89a4d9c871614f5b88eeecbd744d7}, journal = {Nat Commun}, keywords = {imported}, month = {02}, number = 1, pages = 667, timestamp = {2021-01-14T21:21:20.000+0100}, title = {{{A} conserved molecular switch in {C}lass {F} receptors regulates receptor activation and pathway selection}}, volume = 10, year = 2019 }