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bioRxiv · 10.1101/2024.03.12.584619

Structural insights into physiological activation and antagonism of melanin-concentrating hormone receptor MCHR1

Ye, X.·Liu, G.·Li, X.·He, B.·Tao, Y.·Gong, W.·Liu, H.
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Abstract

Melanin-concentrating hormone (MCH) is a 19-amino-acid neuropeptide playing crucial roles in energy homeostasis, sleep, and various physiological processes. It acts through two G protein-coupled receptors, MCHR1 and MCHR2, with MCHR1 being universally present in mammals and a potential target for treating metabolic and mental health conditions. However, drug development efforts have been impeded by the lack of structural information. Here, we present the cryo-EM structures of MCHR1 in its active state complexed with MCH and Gi1, as well as in its inactive state bound to a selective antagonist SNAP-94847. Structural and mutagenesis analyses disclosed the recognition mechanisms for both MCH and SNAP-94847, the activation mechanism and antagonism of MCHR1, and the determinants of ligand specificity. These findings are expected to accelerate the development of better drugs targeting the MCH system.

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Ye, X., Liu, G., Li, X., He, B., Tao, Y., Gong, W., Liu, H.. 2024-03-12. Structural insights into physiological activation and antagonism of melanin-concentrating hormone receptor MCHR1. https://doi.org/10.1101/2024.03.12.584619

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