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

Wenjing Sun; Fan Yang; Huanhuan Zhang; Qingning Yuan; Shenglong Ling; Yuanxia Wang; Pei Lv; Zelin Li; Yifan Luo; Dongsheng Liu; Wanchao Yin; Pan Shi; H Eric Xu; Changlin Tian

doi:10.1038/s41421-023-00564-w

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

Cell Discov. 2023 Jun 30;9(1):66. doi: 10.1038/s41421-023-00564-w.

Authors

Wenjing Sun^#¹, Fan Yang^#¹, Huanhuan Zhang^#¹, Qingning Yuan^#², Shenglong Ling¹, Yuanxia Wang¹, Pei Lv¹, Zelin Li¹, Yifan Luo¹, Dongsheng Liu³, Wanchao Yin^{4

5

6}, Pan Shi⁷, H Eric Xu^{8

9

10}, Changlin Tian^{11

12

13}

Affiliations

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.
² State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
³ iHuman Institute, ShanghaiTech University, Shanghai, China.
⁴ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. wcyin@simm.ac.cn.
⁵ Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, Guangdong, China. wcyin@simm.ac.cn.
⁶ University of Chinese Academy of Sciences, Beijing, China. wcyin@simm.ac.cn.
⁷ 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. shipan@ustc.edu.cn.
⁸ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. eric.xu@simm.ac.cn.
⁹ University of Chinese Academy of Sciences, Beijing, China. eric.xu@simm.ac.cn.
¹⁰ School of Life Science and Technology, ShanghaiTech University, Shanghai, China. eric.xu@simm.ac.cn.
¹¹ 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. cltian@ustc.edu.cn.
¹² State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. cltian@ustc.edu.cn.
¹³ The Anhui Provincial Key Laboratory of High Magnetic Resonance Image, High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, Anhui, China. cltian@ustc.edu.cn.

^# Contributed equally.

Abstract

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-G_q complex bound to NKB, SP and senktide. The three NK3R-G_q/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.

Abstract

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