The relaxin receptor RXFP1 signals through a mechanism of autoinhibition

Nat Chem Biol. 2023 Aug;19(8):1013-1021. doi: 10.1038/s41589-023-01321-6. Epub 2023 Apr 20.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cryoelectron Microscopy
  • Humans
  • Receptors, G-Protein-Coupled / metabolism
  • Receptors, Peptide / chemistry
  • Relaxin* / chemistry
  • Relaxin* / metabolism

Substances

  • relaxin receptors
  • Relaxin
  • Receptors, G-Protein-Coupled
  • Receptors, Peptide
  • RXFP1 protein, human