Structural insights into ligand recognition and activation of melanin-concentrating hormone receptor MCHR1

Abstract Melanin-concentrating hormone (MCH) is a 19-amino acid cyclic neuropeptide playing a crucial role in energy homeostasis, sleep, and other physiological functions. In rodents and humans, MCH promotes feeding through the G protein-coupled receptor MCHR1, making it a promising therapeutical target for metabolic disorders. However, mechanisms for ligand recognition and activation of MCHR1 remains obscure due to the lack of structural information. In this study, we report the cryo-EM structures of MCHR1-Gi1 complex in the MCH-bound state and the ligand-free state. We revealed the specific recognition mechanism of MCH by MCHR1 as well as multiple conformational states of the signaling complex. Distinct distribution of different states in the presence and absence of MCH highlights the relevance of conformational tuning of the complex in MCHR1 activation. Our study provides structural insights into ligand recognition and activation mechanisms of MCHR1 and will facilitate the development of drugs targeting the MCH system.