Targeting G protein-coupled receptor signaling at the G protein level with a selective nanobody inhibitor.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 29777099.
- Also identified by DOI 10.1038/s41467-018-04432-0 and PMC identifier 5959942.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
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 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 Gβγ dimer. Nb5 responds to all combinations of β-subtypes and γ-subtypes and competes with other Gβγ-regulatory proteins for a common binding site on the Gβγ dimer. Despite its inhibitory effect on Gβγ-mediated signaling, Nb5 has no effect on Gα<sub>q</sub>-mediated and Gα<sub>s</sub>-mediated signaling events in living cells.
Medical subject headings
- GTP-Binding Protein alpha Subunits
- GTP-Binding Protein beta Subunits
- GTP-Binding Protein gamma Subunits
- Single-Domain Antibodies