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Targeting G protein-coupled receptor signaling at the G protein level with a selective nanobody inhibitor.

ABSTRACT: G protein-coupled receptors (GPCRs) activate heterotrimeric G proteins by mediating a GDP to GTP exchange in the G? subunit. This leads to dissociation of the heterotrimer into G?-GTP and G?? dimer. The G?-GTP and G?? dimer each regulate a variety of downstream pathways to control various aspects of human physiology. Dysregulated G??-signaling is a central element of various neurological and cancer-related anomalies. However, G?? also serves as a negative regulator of G? that is essential for G protein inactivation, and thus has the potential for numerous side effects when targeted therapeutically. Here we report a llama-derived nanobody (Nb5) that binds tightly to the G?? dimer. Nb5 responds to all combinations of ?-subtypes and ?-subtypes and competes with other G??-regulatory proteins for a common binding site on the G?? dimer. Despite its inhibitory effect on G??-mediated signaling, Nb5 has no effect on G?q-mediated and G?s-mediated signaling events in living cells.

SUBMITTER: Gulati S 

PROVIDER: S-EPMC5959942 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Targeting G protein-coupled receptor signaling at the G protein level with a selective nanobody inhibitor.

Gulati Sahil S   Jin Hui H   Masuho Ikuo I   Orban Tivadar T   Cai Yuan Y   Pardon Els E   Martemyanov Kirill A KA   Kiser Philip D PD   Stewart Phoebe L PL   Ford Christopher P CP   Steyaert Jan J   Palczewski Krzysztof K  

Nature communications 20180518 1

G protein-coupled receptors (GPCRs) activate heterotrimeric G proteins by mediating a GDP to GTP exchange in the Gα subunit. This leads to dissociation of the heterotrimer into Gα-GTP and Gβγ dimer. The Gα-GTP and Gβγ dimer each regulate a variety of downstream pathways to control various aspects of human physiology. Dysregulated Gβγ-signaling is a central element of various neurological and cancer-related anomalies. However, Gβγ also serves as a negative regulator of Gα that is essential for G  ...[more]

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