Structural insights into differences in G protein activation by family A and family B GPCRs.
basic_science · Level V
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- Record sourced from PubMed, PMID 32732395.
- Also identified by DOI 10.1126/science.aba3373 and PMC identifier 7954662.
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Abstract
Family B heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) play important roles in carbohydrate metabolism. Recent structures of family B GPCR-G<sub>s</sub> protein complexes reveal a disruption in the α-helix of transmembrane segment 6 (TM6) not observed in family A GPCRs. To investigate the functional impact of this structural difference, we compared the structure and function of the glucagon receptor (GCGR; family B) with the β<sub>2</sub> adrenergic receptor (β<sub>2</sub>AR; family A). We determined the structure of the GCGR-G<sub>s</sub> complex by means of cryo-electron microscopy at 3.1-angstrom resolution. This structure shows the distinct break in TM6. Guanosine triphosphate (GTP) turnover, guanosine diphosphate release, GTP binding, and G protein dissociation studies revealed much slower rates for G protein activation by the GCGR compared with the β<sub>2</sub>AR. Fluorescence and double electron-electron resonance studies suggest that this difference is due to the inability of agonist alone to induce a detectable outward movement of the cytoplasmic end of TM6.
Medical subject headings
- GTP-Binding Protein alpha Subunits, Gs
- Receptors, Adrenergic, beta-2
- Receptors, Glucagon