Structural insights into G protein-coupled receptor signaling

TL;DR

This paper explores how different types of molecules affect the structure and signaling of G protein-coupled receptors, which are important drug targets.

Contribution

The study reveals how protein ligands and small molecule drugs regulate GPCR activation differently using two receptor models.

Findings

Antibody fragments can stabilize unique conformations of the AT1R and act as competitive or allosteric inhibitors.

A small molecule drug candidate induces different conformational changes and signaling outputs in RXFP1 compared to its native ligand.

The findings highlight both shared and divergent mechanisms of GPCR regulation by different types of ligands.

Abstract

G protein-coupled receptors (GPCRs) are the largest single family of transmembrane proteins encoded in the human genome, and they are among the most successful classes of therapeutic drug targets of all time. Signaling by GPCRs relies on an intricate relay of conformational changes that can be induced, stabilized, or prevented by ligands. Using the angiotensin II type 1 receptor (AT1R) and the RXFP1 relaxin receptor as model systems, we investigated how protein ligands and small molecule drugs differentially regulate receptor activation and signaling outputs. In the case of AT1R we find that antibody fragments can selectively stabilize unique conformations and act as either competitive or allosteric inhibitors. In the case of RXFP1, we find that a small molecule drug candidate induces distinct conformational changes and different signaling outputs than the native ligand relaxin-2. Collectively, these results shed light on shared and divergent aspects of GPCR conformational regulation by protein and small molecule binders, with implications for next-generation GPCR-targeted drug discovery efforts.