Structural basis of the ligand binding and signaling mechanism of melatonin receptors

Qinggong Wang, Qiuyuan Lu, Qiong Guo, Maikun Teng, Qingguo Gong, Xu Li, Yang Du (), Zheng Liu () and Yuyong Tao ()
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Qinggong Wang: University of Science and Technology of China
Qiuyuan Lu: Chinese University of Hong Kong
Qiong Guo: University of Science and Technology of China
Maikun Teng: University of Science and Technology of China
Qingguo Gong: University of Science and Technology of China
Xu Li: University of Science and Technology of China
Yang Du: Chinese University of Hong Kong
Zheng Liu: Chinese University of Hong Kong
Yuyong Tao: University of Science and Technology of China

Nature Communications, 2022, vol. 13, issue 1, 1-10

Abstract: Abstract Melatonin receptors (MT1 and MT2 in humans) are family A G protein–coupled receptors that respond to the neurohormone melatonin to regulate circadian rhythm and sleep. Numerous efforts have been made to develop drugs targeting melatonin receptors for the treatment of insomnia, circadian rhythm disorder, and cancer. However, designing subtype-selective melatonergic drugs remains challenging. Here, we report the cryo-EM structures of the MT1–Gi signaling complex with 2-iodomelatonin and ramelteon and the MT2–Gi signaling complex with ramelteon. These structures, together with the reported functional data, reveal that although MT1 and MT2 possess highly similar orthosteric ligand-binding pockets, they also display distinctive features that could be targeted to design subtype-selective drugs. The unique structural motifs in MT1 and MT2 mediate structural rearrangements with a particularly wide opening on the cytoplasmic side. Gi is engaged in the receptor core shared by MT1 and MT2 and presents a conformation deviating from those in other Gi complexes. Together, our results provide new clues for designing melatonergic drugs and further insights into understanding the G protein coupling mechanism.

Date: 2022
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DOI: 10.1038/s41467-022-28111-3

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