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TitleStructural insights into adhesion GPCR ADGRL3 activation and G, G, G, and G coupling.
Journal, issue, pagesMol Cell, Vol. 82, Issue 22, Page 4340-44352.e6, Year 2022
Publish dateNov 17, 2022
AuthorsYu Qian / Zhengxiong Ma / Chunhong Liu / Xinzhi Li / Xinyan Zhu / Na Wang / Zhenmei Xu / Ruixue Xia / Jiale Liang / Yaning Duan / Han Yin / Yangjie Xiong / Anqi Zhang / Changyou Guo / Zheng Chen / Zhiwei Huang / Yuanzheng He /
PubMed AbstractAdhesion G-protein-coupled receptors (aGPCRs) play key roles in a diversity of physiologies. A hallmark of aGPCR activation is the removal of the inhibitory GAIN domain and the dipping of the cleaved ...Adhesion G-protein-coupled receptors (aGPCRs) play key roles in a diversity of physiologies. A hallmark of aGPCR activation is the removal of the inhibitory GAIN domain and the dipping of the cleaved stalk peptide into the ligand-binding pocket of receptors; however, the detailed mechanism remains obscure. Here, we present cryoelectron microscopy (cryo-EM) structures of ADGRL3 in complex with G, G, G, and G. The structures reveal unique ligand-engaging mode, distinctive activation conformation, and key mechanisms of aGPCR activation. The structures also reveal the uncharted structural information of GPCR/G coupling. A comparison of G, G, G, and G engagements with ADGRL3 reveals the key determinant of G-protein coupling on the far end of αH5 of Gα. A detailed analysis of the engagements allows us to design mutations that specifically enhance one pathway over others. Taken together, our study lays the groundwork for understanding aGPCR activation and G-protein-coupling selectivity.
External linksMol Cell / PubMed:36309016
MethodsEM (single particle)
Resolution2.83 - 2.97 Å
Structure data

EMDB-32884, PDB-7wy5:
ADGRL3/Gq complex
Method: EM (single particle) / Resolution: 2.83 Å

EMDB-32887, PDB-7wy8:
ADGRL3/Gs complex
Method: EM (single particle) / Resolution: 2.83 Å

EMDB-32890, PDB-7wyb:
ADGRL3/Gi complex
Method: EM (single particle) / Resolution: 2.97 Å

EMDB-32932, PDB-7x10:
ADGRL3/miniG12 complex
Method: EM (single particle) / Resolution: 2.93 Å

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
  • lama glama (llama)
KeywordsMEMBRANE PROTEIN / GPCR

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