# Structures of active melanocortin-4 receptor–Gs-protein complexes with NDP-α-MSH and setmelanotide

## TL;DR

This paper reveals the 3D structures of the MC4R receptor bound to two anti-obesity drugs, providing insights into how these drugs activate the receptor and influence signaling.

## Contribution

The study provides high-resolution structures of MC4R–Gs-protein complexes with FDA-approved drugs and reveals the molecular mechanisms of receptor activation.

## Key findings

- Cryo-EM structures of MC4R–Gs complexes with NDP-α-MSH and setmelanotide were resolved at 2.9 Å and 2.6 Å.
- The transmembrane helix 6 and TM3 play key roles in agonist-induced receptor activation and ligand-specific interactions.
- Calcium ions act as a ligand-adaptable cofactor, influencing receptor–Gs-protein interfaces and signaling profiles.

## Abstract

The melanocortin-4 receptor (MC4R), a hypothalamic master regulator of energy homeostasis and appetite, is a class A G-protein-coupled receptor and a prime target for the pharmacological treatment of obesity. Here, we present cryo-electron microscopy structures of MC4R–Gs-protein complexes with two drugs recently approved by the FDA, the peptide agonists NDP-α-MSH and setmelanotide, with 2.9 Å and 2.6 Å resolution. Together with signaling data from structure-derived MC4R mutants, the complex structures reveal the agonist-induced origin of transmembrane helix (TM) 6-regulated receptor activation. The ligand-binding modes of NDP-α-MSH, a high-affinity linear variant of the endogenous agonist α-MSH, and setmelanotide, a cyclic anti-obesity drug with biased signaling toward Gq/11, underline the key role of TM3 in ligand-specific interactions and of calcium ion as a ligand-adaptable cofactor. The agonist-specific TM3 interplay subsequently impacts receptor–Gs-protein interfaces at intracellular loop 2, which also regulates the G-protein coupling profile of this promiscuous receptor. Finally, our structures reveal mechanistic details of MC4R activation/inhibition, and provide important insights into the regulation of the receptor signaling profile which will facilitate the development of tailored anti-obesity drugs.