Structure-guided optimization of light-activated chimeric G-protein-coupled receptors

Alexandra Madelaine Tichy, Wang Lok So, Elliot J. Gerrard, Harald Janovjak

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

G-protein-coupled receptors (GPCRs) are the largest human receptor family and involved in virtually every physiological process. One hallmark of their function is specific coupling to selected signaling pathways. The ability to tune this coupling would make development of receptors with new capabilities possible. Complexes of GPCRs and G-proteins have recently been resolved at high resolution, but this information was in only few cases harnessed for rational receptor engineering. Here, we demonstrate structure-guided optimization of light-activated OptoXRs. Our hypothesis was that incorporation of GPCR-Gα contacts would lead to improved coupling. We first evaluated structure-based alignments for chimeric receptor fusion. We then show in a light-activated β2AR that including Gα contacts increased signaling 7- to 20-fold compared with other designs. In turn, contact elimination diminished function. Finally, this platform allowed optimization of a further OptoXR and spectral tuning. Our work exemplifies structure-based OptoXR development for targeted cell and network manipulation.

Original languageEnglish
Pages (from-to)1075-1087.e4
Number of pages17
JournalSTRUCTURE
Volume30
Issue number8
DOIs
Publication statusPublished - 4 Aug 2022

Keywords

  • cell signaling
  • G-protein-coupled receptor
  • optogenetics
  • protein engineering

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