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The relaxin receptor RXFP1 signals through a mechanism of autoinhibition.
Erlandson, Sarah C; Rawson, Shaun; Osei-Owusu, James; Brock, Kelly P; Liu, Xinyue; Paulo, Joao A; Mintseris, Julian; Gygi, Steven P; Marks, Debora S; Cong, Xiaojing; Kruse, Andrew C.
Afiliación
  • 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.
Nat Chem Biol ; 19(8): 1013-1021, 2023 08.
Article en En | MEDLINE | ID: mdl-37081311
ABSTRACT
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 Gs 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.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Relaxina Límite: Humans Idioma: En Revista: Nat Chem Biol Asunto de la revista: BIOLOGIA / QUIMICA Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Relaxina Límite: Humans Idioma: En Revista: Nat Chem Biol Asunto de la revista: BIOLOGIA / QUIMICA Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos