8JGB

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

Summary for 8JGB

• Entry DOI: 10.2210/pdb8jgb/pdb
• EMDB information: 36229
• Descriptor: 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)
• Functional Keywords: itch receptor, mas-related gpcrs, mgprx1, structural protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 154819.74

Authors

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. (deposition date: 2023-05-20, release date: 2024-01-10)

Primary citation

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

Experimental method

ELECTRON MICROSCOPY (2.84 Å)