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Title | Tethered peptide activation mechanism of the adhesion GPCRs ADGRG2 and ADGRG4. |
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Journal, issue, pages | Nature, Vol. 604, Issue 7907, Page 771-778, Year 2022 |
Publish date | Apr 13, 2022 |
Authors | Peng Xiao / Shengchao Guo / Xin Wen / Qing-Tao He / Hui Lin / Shen-Ming Huang / Lu Gou / Chao Zhang / Zhao Yang / Ya-Ni Zhong / Chuan-Cheng Yang / Yu Li / Zheng Gong / Xiao-Na Tao / Zhi-Shuai Yang / Yan Lu / Shao-Long Li / Jun-Yan He / Chuanxin Wang / Lei Zhang / Liangliang Kong / Jin-Peng Sun / Xiao Yu / |
PubMed Abstract | Adhesion G protein-coupled receptors (aGPCRs) constitute an evolutionarily ancient family of receptors that often undergo autoproteolysis to produce α and β subunits. A tethered agonism mediated by ...Adhesion G protein-coupled receptors (aGPCRs) constitute an evolutionarily ancient family of receptors that often undergo autoproteolysis to produce α and β subunits. A tethered agonism mediated by the 'Stachel sequence' of the β subunit has been proposed to have central roles in aGPCR activation. Here we present three cryo-electron microscopy structures of aGPCRs coupled to the G heterotrimer. Two of these aGPCRs are activated by tethered Stachel sequences-the ADGRG2-β-G complex and the ADGRG4-β-G complex (in which β indicates the β subunit of the aGPCR)-and the other is the full-length ADGRG2 in complex with the exogenous ADGRG2 Stachel-sequence-derived peptide agonist IP15 (ADGRG2(FL)-IP15-G). The Stachel sequences of both ADGRG2-β and ADGRG4-β assume a U shape and insert deeply into the seven-transmembrane bundles. Constituting the FXφφφXφ motif (in which φ represents a hydrophobic residue), five residues of ADGRG2-β or ADGRG4-β extend like fingers to mediate binding to the seven-transmembrane domain and activation of the receptor. The structure of the ADGRG2(FL)-IP15-G complex reveals the structural basis for the improved binding affinity of IP15 compared with VPM-p15 and indicates that rational design of peptidic agonists could be achieved by exploiting aGPCR-β structures. By converting the 'finger residues' to acidic residues, we develop a method to generate peptidic antagonists towards several aGPCRs. Collectively, our study provides structural and biochemical insights into the tethered activation mechanism of aGPCRs. |
External links | Nature / PubMed:35418677 |
Methods | EM (single particle) |
Resolution | 2.9 - 3.3 Å |
Structure data | EMDB-32836, PDB-7wui: EMDB-32837, PDB-7wuj: EMDB-32838, PDB-7wuq: |
Source |
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Keywords | MEMBRANE PROTEIN / GPCR / ADGRG2 / ADGRG4 |