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Structural Elements Directing G Proteins and ß-Arrestin Interactions with the Human Melatonin Type 2 Receptor Revealed by Natural Variants.
Plouffe, Bianca; Karamitri, Angeliki; Flock, Tilman; Gallion, Jonathan M; Houston, Shane; Daly, Carole A; Bonnefond, Amélie; Guillaume, Jean-Luc; Le Gouill, Christian; Froguel, Phillipe; Lichtarge, Olivier; Deupi, Xavier; Jockers, Ralf; Bouvier, Michel.
Afiliación
  • Plouffe B; Department of Biochemistry and Molecular Medicine, Université de Montréal, H3T 1J4 Montréal, Québec, Canada.
  • Karamitri A; Institute for Research in Immunology and Cancer, Université de Montréal, H3T 1J4 Montréal, Québec, Canada.
  • Flock T; The Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, BT9 7BL Belfast, U.K.
  • Gallion JM; Université de Paris, Institut Cochin, INSERM, CNRS, F-75014 Paris, France.
  • Houston S; Laboratory of Biomolecular Research, Department of Biology and Chemistry, Paul Scherrer Institute, 5232 Villigen, Switzerland.
  • Daly CA; Department of Biology, ETH Zürich, 8093 Zürich, Switzerland.
  • Bonnefond A; Program in Structural and Computational Biology and Molecular Biophysics, Baylor College of Medicine, 77030 Houston, Texas, United States.
  • Guillaume JL; The Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, BT9 7BL Belfast, U.K.
  • Le Gouill C; The Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, BT9 7BL Belfast, U.K.
  • Froguel P; Université de Lille, INSERM/CNRS UMR 1283/8199-EGID, Institut Pasteur de Lille, CHU de Lille, 59045 Lille, France.
  • Lichtarge O; Université de Paris, Institut Cochin, INSERM, CNRS, F-75014 Paris, France.
  • Deupi X; Institute for Research in Immunology and Cancer, Université de Montréal, H3T 1J4 Montréal, Québec, Canada.
  • Jockers R; Université de Lille, INSERM/CNRS UMR 1283/8199-EGID, Institut Pasteur de Lille, CHU de Lille, 59045 Lille, France.
  • Bouvier M; Program in Structural and Computational Biology and Molecular Biophysics, Baylor College of Medicine, 77030 Houston, Texas, United States.
ACS Pharmacol Transl Sci ; 5(2): 89-101, 2022 Feb 11.
Article en En | MEDLINE | ID: mdl-35846981
G protein-coupled receptors (GPCRs) can engage distinct subsets of signaling pathways, but the structural determinants of this functional selectivity remain elusive. The naturally occurring genetic variants of GPCRs, selectively affecting different pathways, offer an opportunity to explore this phenomenon. We previously identified 40 coding variants of the MTNR1B gene encoding the melatonin MT2 receptor (MT2). These mutations differently impact the ß-arrestin 2 recruitment, ERK activation, cAMP production, and Gαi1 and Gαz activation. In this study, we combined functional clustering and structural modeling to delineate the molecular features controlling the MT2 functional selectivity. Using non-negative matrix factorization, we analyzed the signaling signatures of the 40 MT2 variants yielding eight clusters defined by unique signaling features and localized in distinct domains of MT2. Using computational homology modeling, we describe how specific mutations can selectively affect the subsets of signaling pathways and offer a proof of principle that natural variants can be used to explore and understand the GPCR functional selectivity.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Prognostic_studies Idioma: En Revista: ACS Pharmacol Transl Sci Año: 2022 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Prognostic_studies Idioma: En Revista: ACS Pharmacol Transl Sci Año: 2022 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Estados Unidos