8jgb
CryoEM structure of Gi-coupled MRGPRX1 with peptide agonist CNF-Tx2
Structural highlights
FunctionCRFA2_CONTE This peptide activates human sensory neuron-specific G-protein coupled receptors MRGPRX1, but not mouse receptors (EC(50)=0.54 uM) (PubMed:30243794). Compared with the agonist chloroquine (anti-malaria drug), it is 600-fold more potent (PubMed:30243794). In vivo, induces itch sensation, since intradermal cheek injection into humanized transgenic mouse (mouse MRGPRX1 replaced by human MRGPRX1) induces scratching (PubMed:30243794). In vivo, treatment of zebrafish larvae with high doses (10 uM) induces hypoactivity at the beginning of the experiment during the dark phase and hyperactivity in the strobe phase after one hour, even after the removal of the toxin from the solution (PubMed:33764053).[1] [2] Publication Abstract from PubMedMRGPRX1, 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 G(6.48)XP(6.50)F(6.51)G(6.52)X((2))F/W(6.55) 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. Ligand recognition and G protein coupling of the human itch receptor MRGPRX1.,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 JP Nat Commun. 2023 Aug 17;14(1):5004. doi: 10.1038/s41467-023-40705-z. PMID:37591889[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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