The relaxin receptor RXFP1 signals through a mechanism of autoinhibition.

Autor: Erlandson SC; Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA., Rawson S; Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA., Osei-Owusu J; Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA., Brock KP; Department of Systems Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA., Liu X; Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA., Paulo JA; Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA., Mintseris J; Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA., Gygi SP; Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA., Marks DS; Department of Systems Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA., Cong X; Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, France., Kruse AC; Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA. andrew_kruse@hms.harvard.edu.
Jazyk: angličtina
Zdroj: Nature chemical biology [Nat Chem Biol] 2023 Aug; Vol. 19 (8), pp. 1013-1021. Date of Electronic Publication: 2023 Apr 20.
DOI: 10.1038/s41589-023-01321-6
Abstrakt: The relaxin family peptide receptor 1 (RXFP1) is the receptor for relaxin-2, an important regulator of reproductive and cardiovascular physiology. RXFP1 is a multi-domain G protein-coupled receptor (GPCR) with an ectodomain consisting of a low-density lipoprotein receptor class A (LDLa) module and leucine-rich repeats. The mechanism of RXFP1 signal transduction is clearly distinct from that of other GPCRs, but remains very poorly understood. In the present study, we determine the cryo-electron microscopy structure of active-state human RXFP1, bound to a single-chain version of the endogenous agonist relaxin-2 and the heterotrimeric G s protein. Evolutionary coupling analysis and structure-guided functional experiments reveal that RXFP1 signals through a mechanism of autoinhibition. Our results explain how an unusual GPCR family functions, providing a path to rational drug development targeting the relaxin receptors.
(© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Databáze: MEDLINE
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