G protein coupling and activation of the metabotropic GABA<sub>B</sub> heterodimer.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 35941188.
- Also identified by DOI 10.1038/s41467-022-32213-3 and PMC identifier 9360005.
- 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
Metabotropic γ-aminobutyric acid receptor (GABA<sub>B</sub>R), a class C G protein-coupled receptor (GPCR) heterodimer, plays a crucial role in the central nervous system. Cryo-electron microscopy studies revealed a drastic conformational change upon activation and a unique G protein (GP) binding mode. However, little is known about the mechanism for GP coupling and activation for class C GPCRs. Here, we use molecular metadynamics computations to predict the mechanism by which the inactive GP induces conformational changes in the GABA<sub>B</sub>R transmembrane domain (TMD) to form an intermediate pre-activated state. We find that the inactive GP first interacts with TM3, which further leads to the TMD rearrangement and deeper insertion of the α5 helix that causes the Gα subunit to open, releasing GDP, and forming the experimentally observed activated structure. This mechanism provides fresh insights into the mechanistic details of class C GPCRs activation expected to be useful for designing selective agonists and antagonists.
Medical subject headings
- GTP-Binding Proteins
- gamma-Aminobutyric Acid