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

• DOI: 10.1038/s41421-023-00564-w
• Publication Date: 2023-06-30T14:02:42Z
• 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
• Keywords: Neurokinin B; Neurokinin A

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