Journal Article

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

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

2024

Overview

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.

• Publisher: Springer Nature Singapore,Springer Nature B.V,Nature Publishing Group
• Subject: 631/535/1258/1259 / 631/80/86 / Amino acids / Biomedical and Life Sciences / Cell Biology / Cell Culture / Cell Cycle Analysis / Cell Physiology / Drug development / Electron microscopy / Energy balance / Food intake / G protein-coupled receptors / Life Sciences / Ligands / Melanin / Melanin-concentrating hormone / Melanin-concentrating hormone receptors / Neuropeptides / Obesity / Physiology / Proteins / Receptor mechanisms / Stem Cells