Structural insights into physiological activation and antagonism of melanin-concentrating hormone receptor MCHR1
Year: 2024
Type: article
Abstract: Melanin-concentrating hormone (MCH) is a 19-amino-acid neuropeptide playing crucial roles in energy homeostasis, sleep, and various physiological processes. It acts through two G protein-coupled receptors, MCHR1 and MCHR2, with MCHR1 being universally present in mammals and a potential target for treating metabolic and mental health conditions. However, drug development efforts have been impeded by the lack of structural information. Here, we present the cryo-EM structures of MCHR1 in its active state complexed with MCH and G i1 , as well as in its inactive state bound to a selective antagonist SNAP-94847. Structural and mutagenesis analyses disclosed the recognition mechanisms for both MCH and SNAP-94847, the activation mechanism and antagonism of MCHR1, and the determinants of ligand specificity. These findings are expected to accelerate the development of better drugs targeting the MCH system.
Source: Cell Discovery
Authors: Xiaofan Ye, Guibing Liu, Xiu Li, Binbin He, Yuyong Tao, Jiasheng Guan, Yuguang Mu, Haiping Liu, Weimin Gong
Institution: University of Science and Technology of China
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,390
OpenAlex ID: W4404874705