Structure of an endosomal signaling GPCR–G protein–β-arrestin megacomplex

Anthony H. Nguyen, Alex R.B. Thomsen, Thomas J. Cahill, Rick Huang, Li Yin Huang, Tara Marcink, Oliver B. Clarke, Søren Heissel, Ali Masoudi, Danya Ben-Hail, Fadi Samaan, Venkata P. Dandey, Yong Zi Tan, Chuan Hong, Jacob P. Mahoney, Sarah Triest, John Little, Xin Chen, Roger Sunahara, Jan SteyaertHenrik Molina, Zhiheng Yu, Amedee des Georges, Robert J. Lefkowitz

Research output: Contribution to journalArticlepeer-review


Classically, G-protein-coupled receptors (GPCRs) are thought to activate G protein from the plasma membrane and are subsequently desensitized by β-arrestin (β-arr). However, some GPCRs continue to signal through G protein from internalized compartments, mediated by a GPCR–G protein–β-arr ‘megaplex’. Nevertheless, the molecular architecture of the megaplex remains unknown. Here, we present its cryo-electron microscopy structure, which shows simultaneous engagement of human G protein and bovine β-arr to the core and phosphorylated tail, respectively, of a single active human chimeric β2-adrenergic receptor with the C-terminal tail of the arginine vasopressin type 2 receptor (β2V2R). All three components adopt their canonical active conformations, suggesting that a single megaplex GPCR is capable of simultaneously activating G protein and β-arr. Our findings provide a structural basis for GPCR-mediated sustained internalized G protein signaling.

Original languageEnglish (US)
Pages (from-to)1123-1131
Number of pages9
JournalNature Structural and Molecular Biology
Issue number12
StatePublished - Dec 1 2019

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology


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