RT Journal Article
SR Electronic
T1 The relaxin receptor RXFP1 signals through a mechanism of autoinhibition
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.01.22.477343
DO 10.1101/2022.01.22.477343
A1 Sarah C. Erlandson
A1 Shaun Rawson
A1 Kelly P. Brock
A1 Xinyue Liu
A1 Joao A. Paulo
A1 Julian Mintseris
A1 Steven P. Gygi
A1 Debora S. Marks
A1 Xiaojing Cong
A1 Andrew C. Kruse
YR 2022
UL http://biorxiv.org/content/early/2022/01/26/2022.01.22.477343.abstract
AB The relaxin family peptide receptor 1 (RXFP1) is the receptor for relaxin-2, an important regulator of reproductive and cardiovascular physiology and an established therapeutic target. RXFP1 is a multi-domain G protein-coupled receptor (GPCR) with an ectodomain consisting of an LDLa module and leucine-rich repeats. The molecular mechanism of RXFP1 signal transduction is clearly distinct from that of other GPCRs, but remains very poorly understood, hindering the development of therapeutics targeting the receptor. Here we present the cryo-electron microscopy structure of active-state human RXFP1, bound to the endogenous agonist relaxin-2 and heterotrimeric Gs proteins. Evolutionary coupling analysis and structure-guided functional experiments reveal that RXFP1 signals through a mechanism of autoinhibition, wherein the receptor’s extracellular loop 2 occupies the orthosteric site in the active state but is inhibited by the ectodomain in the absence of relaxin-2. Together, these data provide a model for relaxin receptor signaling, explaining how an unusual but important GPCR sub-family functions and providing a path to rational drug development targeting the relaxin receptors.Competing Interest StatementA.C.K. and S.C.E are inventors on a patent application for engineered single-chain relaxin proteins. A.C.K. is a co-founder and consultant for Tectonic Therapeutic and Seismic Therapeutic and for the Institute for Protein Innovation, a non-profit research institute.