8JBH

Substance P bound to active human neurokinin 3 receptor in complex with Gq

これはPDB形式変換不可エントリーです。

8JBH の概要

• エントリーDOI: 10.2210/pdb8jbh/pdb
• EMDBエントリー: 36146
• 分子名称: NK3R-pFastbac1, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, ScFv16 nanobody, ... (6 entities in total)
• 機能のキーワード: g protein coupled receptor, neurokinin, cryo-em, peptide agonists, membrane protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 282759.93

構造登録者

Sun, W.J.,Yang, F.,Zhang, H.H.,Yuan, Q.N.,Yin, W.C.,Shi, P.,Eric, X.,Tian, C.L. (登録日: 2023-05-08, 公開日: 2024-02-07)

主引用文献

Sun, W.,Yang, F.,Zhang, H.,Yuan, Q.,Ling, S.,Wang, Y.,Lv, P.,Li, Z.,Luo, Y.,Liu, D.,Yin, W.,Shi, P.,Xu, H.E.,Tian, C.
Structural insights into neurokinin 3 receptor activation by endogenous and analogue peptide agonists.
Cell Discov, 9:66-66, 2023

PubMed 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.

PubMed: 37391393
DOI: 10.1038/s41421-023-00564-w

実験手法

ELECTRON MICROSCOPY (2.9 Å)