Structural Insights into Neurokinin 3 Receptor Activation by Endogenous and Analogue Peptide Agonists

Overview

Journal Cell Discov

Date 2023 Jun 30

PMID 37391393

Authors

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

Affiliations

Soon will be listed here.

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

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