Structural insights into neurokinin 3 receptor activation by endogenous and analogue peptide agonists

Cell Discovery

Article

Yifan Luo¹  Wenjing Sun¹  Pan Shi¹  Zelin Li¹  Yuanxia Wang¹  Shenglong Ling¹  Huanhuan Zhang¹  Fan Yang¹  Pei Lv¹  Changlin Tian²  Qingning Yuan³  H. Eric Xu⁴  Wanchao Yin⁵  Dongsheng Liu⁶ 

[1] Department of Endocrinology, Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital of USTC, School of Life Sciences, Division of Life Sciences and Medicine, Joint Center for Biological Analytical Chemistry, Anhui Engineering Laboratory of Peptide Drug, Anhui Laboratory of Advanced Photonic Science and Technology, University of Science and Technology of China, Hefei, Anhui, China;Department of Endocrinology, Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital of USTC, School of Life Sciences, Division of Life Sciences and Medicine, Joint Center for Biological Analytical Chemistry, Anhui Engineering Laboratory of Peptide Drug, Anhui Laboratory of Advanced Photonic Science and Technology, University of Science and Technology of China, Hefei, Anhui, China;State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China;The Anhui Provincial Key Laboratory of High Magnetic Resonance Image, High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, Anhui, China;State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China;State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China;University of Chinese Academy of Sciences, Beijing, China;School of Life Science and Technology, ShanghaiTech University, Shanghai, China;State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China;Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, Guangdong, China;University of Chinese Academy of Sciences, Beijing, China;iHuman Institute, ShanghaiTech University, Shanghai, China;

关键词: ;   

DOI  :  10.1038/s41421-023-00564-w

 received in 2022-12-31, accepted in 2023-05-12,  发布年份 2023

来源: Springer

【 摘 要 】

Neurokinin 3 receptor (NK3R) is a tachykinin receptor essential for the hypothalamic-pituitary-gonadal axis. The endogenous peptide agonist neurokinin B (NKB) preferentially activates NK3R, while substance P (SP) binds preferentially to NK1R. In addition, the SP analogue senktide more potently activates NK3R than NKB and SP. However, the mechanisms of preferential binding of peptide and NK3R activation remain elusive. Herein, we determined the cryogenic electron microscopy (cryo-EM) structures of the NK3R–Gq complex bound to NKB, SP and senktide. The three NK3R–Gq/peptide complexes utilize a class of noncanonical receptor activation mechanisms. Combining the structural analysis and functional assay illustrated that the consensus C-termini of the three peptide agonists share a conserved binding mode to NK3R, while the divergent N-termini of the peptides confer the preferential binding of the agonist to NK3R. In addition, the specific interactions between the N-terminus of senktide and the N-terminus and extracellular loops (ECL2 and ECL3) of NK3R lead to the improved activation displayed by senktide compared to SP and NKB. These findings pave the way to understand tachykinin receptor subtype selectivity and provide ideas to rationally develop drugs targeting NK3R.

【 授权许可】

CC BY   
© The Author(s) 2023

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