Mechanisms of ligand recognition and activation of melanin-concentrating hormone receptors

Qian He; Qingning Yuan; Hong Shan; Canrong Wu; Yimin Gu; Kai Wu; Wen Hu; Yumu Zhang; Xinheng He; H Eric Xu; Li-Hua Zhao

doi:10.1038/s41421-024-00679-8

Mechanisms of ligand recognition and activation of melanin-concentrating hormone receptors

Cell Discov. 2024 May 7;10(1):48. doi: 10.1038/s41421-024-00679-8.

Authors

Qian He^#^{1

2}, Qingning Yuan^#³, Hong Shan¹, Canrong Wu¹, Yimin Gu¹, Kai Wu¹, Wen Hu¹, Yumu Zhang¹, Xinheng He^{1

2}, H Eric Xu^{4

5}, Li-Hua Zhao^{6

7}

Affiliations

¹ State Key Laboratory of Drug Research, Center for Structure and Function of Drug Targets, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
² University of Chinese Academy of Sciences, Beijing, China.
³ College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
⁴ State Key Laboratory of Drug Research, Center for Structure and Function of Drug Targets, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. eric.xu@simm.ac.cn.
⁵ University of Chinese Academy of Sciences, Beijing, China. eric.xu@simm.ac.cn.
⁶ State Key Laboratory of Drug Research, Center for Structure and Function of Drug Targets, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. zhaolihuawendy@simm.ac.cn.
⁷ University of Chinese Academy of Sciences, Beijing, China. zhaolihuawendy@simm.ac.cn.

^# Contributed equally.

Abstract

Melanin-concentrating hormone (MCH) is a cyclic neuropeptide that regulates food intake, energy balance, and other physiological functions by stimulating MCHR1 and MCHR2 receptors, both of which are class A G protein-coupled receptors. MCHR1 predominately couples to inhibitory G protein, G_i/o, and MCHR2 can only couple to G_q/11. Here we present cryo-electron microscopy structures of MCH-activated MCHR1 with G_i and MCH-activated MCHR2 with G_q at the global resolutions of 3.01 Å and 2.40 Å, respectively. These structures reveal that MCH adopts a consistent cysteine-mediated hairpin loop configuration when bound to both receptors. A central arginine from the LGRVY core motif between the two cysteines of MCH penetrates deeply into the transmembrane pocket, triggering receptor activation. Integrated with mutational and functional insights, our findings elucidate the molecular underpinnings of ligand recognition and MCH receptor activation and offer a structural foundation for targeted drug design.