8JGB

CryoEM structure of Gi-coupled MRGPRX1 with peptide agonist CNF-Tx2

8JGB の概要

• エントリーDOI: 10.2210/pdb8jgb/pdb
• EMDBエントリー: 36229
• 分子名称: Conorfamide-Tx2, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, Guanine nucleotide-binding protein G(i) subunit alpha-1, ... (6 entities in total)
• 機能のキーワード: itch receptor, mas-related gpcrs, mgprx1, structural 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: 154819.74

構造登録者

Sun, J.P.,Xu, H.E.,Yang, F.,Liu, Z.M.,Guo, L.L.,Zhang, Y.M.,Fang, G.X.,Tie, L.,Zhuang, Y.M.,Xue, C.Y. (登録日: 2023-05-20, 公開日: 2024-01-10, 最終更新日: 2024-11-20)

主引用文献

Guo, L.,Zhang, Y.,Fang, G.,Tie, L.,Zhuang, Y.,Xue, C.,Liu, Q.,Zhang, M.,Zhu, K.,You, C.,Xu, P.,Yuan, Q.,Zhang, C.,Liu, L.,Rong, N.,Peng, S.,Liu, Y.,Wang, C.,Luo, X.,Lv, Z.,Kang, D.,Yu, X.,Zhang, C.,Jiang, Y.,Dong, X.,Zhou, J.,Liu, Z.,Yang, F.,Eric Xu, H.,Sun, J.P.
Ligand recognition and G protein coupling of the human itch receptor MRGPRX1.
Nat Commun, 14:5004-5004, 2023

PubMed Abstract: MRGPRX1, a Mas-related GPCR (MRGPR), is a key receptor for itch perception and targeting MRGPRX1 may have potential to treat both chronic itch and pain. Here we report cryo-EM structures of the MRGPRX1-Gi1 and MRGPRX1-Gq trimers in complex with two peptide ligands, BAM8-22 and CNF-Tx2. These structures reveal a shallow orthosteric pocket and its conformational plasticity for sensing multiple different peptidic itch allergens. Distinct from MRGPRX2, MRGPRX1 contains a unique pocket feature at the extracellular ends of TM3 and TM4 to accommodate the peptide C-terminal "RF/RY" motif, which could serve as key mechanisms for peptidic allergen recognition. Below the ligand binding pocket, the GXPFGXF/W motif is essential for the inward tilting of the upper end of TM6 to induce receptor activation. Moreover, structural features inside the ligand pocket and on the cytoplasmic side of MRGPRX1 are identified as key elements for both Gi and Gq signaling. Collectively, our studies provide structural insights into understanding itch sensation, MRGPRX1 activation, and downstream G protein signaling.

PubMed: 37591889
DOI: 10.1038/s41467-023-40705-z

実験手法

ELECTRON MICROSCOPY (2.84 Å)