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TitleLigand recognition and G protein coupling of the human itch receptor MRGPRX1.
Journal, issue, pagesNat Commun, Vol. 14, Issue 1, Page 5004, Year 2023
Publish dateAug 17, 2023
AuthorsLulu Guo / Yumu Zhang / Guoxing Fang / Lu Tie / Yuming Zhuang / Chenyang Xue / Qi Liu / Minghui Zhang / Kongkai Zhu / Chongzhao You / Peiyu Xu / Qingning Yuan / Chao Zhang / Lei Liu / Naikang Rong / Shengxuan Peng / Yuan Liu / Chuanzheng Wang / Xin Luo / Zongyao Lv / Dongwei Kang / Xiao Yu / Cheng Zhang / Yi Jiang / Xinzhong Dong / Jiuyao Zhou / Zhongmin Liu / Fan Yang / H Eric Xu / Jin-Peng Sun /
PubMed AbstractMRGPRX1, 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, 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.
External linksNat Commun / PubMed:37591889 / PubMed Central
MethodsEM (single particle)
Resolution2.7 - 3.0 Å
Structure data

EMDB-36229, PDB-8jgb:
CryoEM structure of Gi-coupled MRGPRX1 with peptide agonist CNF-Tx2
Method: EM (single particle) / Resolution: 2.84 Å

EMDB-36232, PDB-8jgf:
CryoEM structure of Gq-coupled MRGPRX1 with peptide agonist BAM8-22
Method: EM (single particle) / Resolution: 2.7 Å

EMDB-36233, PDB-8jgg:
CryoEM structure of Gi-coupled MRGPRX1 with peptide agonist BAM8-22
Method: EM (single particle) / Resolution: 3.0 Å

Source
  • homo sapiens (human)
  • conus textile (cloth-of-gold cone)
KeywordsSTRUCTURAL PROTEIN / itch receptor / Mas-related GPCRs / MGPRX1 / MRGPRX1

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