Structure-guided optimization of light-activated chimeric G-protein-coupled receptors.
Structure
; 30(8): 1075-1087.e4, 2022 08 04.
Article
em En
| MEDLINE
| ID: mdl-35588733
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 ß2AR 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.
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Base de dados:
MEDLINE
Assunto principal:
Proteínas de Ligação ao GTP
/
Receptores Acoplados a Proteínas G
Limite:
Humans
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article