He, Q.; Yuan, Q.; Shan, H.; Wu, C.; Gu, Y.; Wu, K.; Hu, W.; Zhang, Y.; Xu, H. E.; Zhao, L.

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 can couple with multiple G-proteins, including Gi/o, Gq/11, and Gs, while MCHR2 only couple to Gq/11. Here we present cryo-electron microscopy structures of MCH-activated MCHR1 with Gi and MCH-activated MCHR2 with Gq complexes, at the global resolutions of 3.01 [A] and 2.40 [A], respectively. These structures reveal that MCH adopts a consistent cysteine-mediated hairpin loop configuration in 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, offering a structured foundation for targeted drug design.