On May 7th, researchers Xu Huaqiang and Zhao Lihua from the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, utilized cryo-electron microscopy to elucidate the complex structures of human melanin-concentrating hormone receptor 1 (MCHR1) coupled with Gi and MCHR2 coupled with Gq when activated by melanin-concentrating hormone (MCH). This provides a deeper understanding of ligand recognition and receptor activation, offering a structural basis for drug design targeting MCHRs. The related study was published in "Cell Discovery."
The MCH system is considered a promising therapeutic target for diseases such as obesity, depression, and sleep disorders. However, some MCHR1 antagonists under research currently lack specificity, and there are no drugs targeting this receptor clinically. A comprehensive understanding of the structural mechanism of MCH receptor activation is crucial.
Through structural analysis, mutagenesis, and functional assays, the research team validated the ligand binding sites in MCHR1 and MCHR2, revealing the conservation of the clamp structure formed by Cys6 and Cys17 of MCH in the ligand-receptor binding pocket. They discovered that the central arginine of the LGRVY core motif in MCH plays a crucial role in triggering receptor activation and downstream signaling cascades.
Furthermore, utilizing AlphaFold2, the research team predicted the non-activated conformation of the receptor and the activated conformation of the MCH-MCHRs-G protein complex, comparing them with the cryo-electron microscopy structures. AlphaFold2 accurately predicted the overall structure, but showed some differences in predicting the precise conformation of the ligand, receptor structural domains, and G protein conformation.
The structures of the MCH-MCHR1-Gi and MCH-MCHR2-Gq complexes. Image source: Cell Discovery.
Related paper information: https://doi.org/10.1038/s41421-024-00679-8
