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TitleMechanisms of ligand recognition and activation of melanin-concentrating hormone receptors.
Journal, issue, pagesCell Discov, Vol. 10, Issue 1, Page 48, Year 2024
Publish dateMay 7, 2024
AuthorsQian He / Qingning Yuan / Hong Shan / Canrong Wu / Yimin Gu / Kai Wu / Wen Hu / Yumu Zhang / Xinheng He / H Eric Xu / Li-Hua Zhao /
PubMed AbstractMelanin-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 ...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, and MCHR2 can only couple to G. Here we present cryo-electron microscopy structures of MCH-activated MCHR1 with G and MCH-activated MCHR2 with G 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.
External linksCell Discov / PubMed:38710677 / PubMed Central
MethodsEM (single particle)
Resolution2.4 - 3.01 Å
Structure data

37823

8wss

EMDB-37823, PDB-8wss:
Cryo-EM structure of Melanin-Concentrating Hormone Receptor 1 with MCH
Method: EM (single particle) / Resolution: 3.01 Å

37824

8wst

EMDB-37824, PDB-8wst:
Cryo-EM structure of Melanin-Concentrating Hormone Receptor 2 with MCH
Method: EM (single particle) / Resolution: 2.4 Å

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
KeywordsMEMBRANE PROTEIN / Melanin-Concentrating Hormone Receptors1 / GPCR / Melanin-Concentrating Hormone Receptors2

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