ArticleThe Journal of biological chemistry2016
Structural Elements in the Gαs and Gαq C Termini That Mediate Selective G Protein-coupled Receptor (GPCR) Signaling.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 48 citations in OpenAlex.
- Protein Frustration Reveals Orthosteric and Allosteric Active Sites in GPCR:G Protein Complexes.Journal of chemical information and modeling · 2026Article
- The diversity of insecticide target site mutations in Apis mellifera.BMC genomics · 2026Article
- Allostery between Distant Structural Regions Dictates Selectivity in GPCR:G Protein Coupling.Biochemistry · 2026Article
- Structural basis for ligand promiscuity and high signaling activity of Kaposi's Sarcoma-associated Herpesvirus-encoded GPCR.Nature communications · 2025Article
- Efficient in vivo labeling of endogenous proteins with SMART delineates retina cellular and synaptic organization.Nature communications · 2025Article
- Mechanistic insights into G-protein coupling with an agonist-bound G-protein-coupled receptor.Nature structural & molecular biology · 2024Article
- Bayesian network models identify cooperative GPCR:G protein interactions that contribute to G protein coupling.The Journal of biological chemistry · 2024Article
- Molecular mechanism of muscarinic acetylcholine receptor M3 interaction with Gq.Communications biology · 2024Article
- Direct interrogation of context-dependent GPCR activity with a universal biosensor platform.Cell · 2024Article
- Direct interrogation of context-dependent GPCR activity with a universal biosensor platform.bioRxiv : the preprint server for biology · 2024Article
- Bayesian network models identify co-operative GPCR:G protein interactions that contribute to G protein coupling.bioRxiv : the preprint server for biology · 2023Article
- Advancements in G protein-coupled receptor biosensors to study GPCR-G protein coupling.British journal of pharmacology · 2023Review
- Pan-cancer functional analysis of somatic mutations in G protein-coupled receptors.Scientific reports · 2022Article
- Dynamic spatiotemporal determinants modulate GPCR:G protein coupling selectivity and promiscuity.Nature communications · 2022Article
- Evolutionary association of receptor-wide amino acids with G protein-coupling selectivity in aminergic GPCRs.Life science alliance · 2022Article
- Structural insights into galanin receptor signaling.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- The Conformational Dynamics of Heterotrimeric G Proteins During GPCR-Mediated Activation.Sub-cellular biochemistry · 2022Review
- Genetically encoded fluorescent biosensors for GPCR research.Frontiers in cell and developmental biology · 2022Review
- Coevolution underlies GPCR-G protein selectivity and functionality.Scientific reports · 2021Article
- β2-adrenoceptor ligand efficacy is tuned by a two-stage interaction with the Gαs C terminus.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
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Authors and funding
5 authors at 4 institutions in 1 country.
Funding
Abstract
Although the importance of the C terminus of the α subunit of the heterotrimeric G protein in G protein-coupled receptor (GPCR)-G protein pairing is well established, the structural basis of selective interactions remains unknown. Here, we combine live cell FRET-based measurements and molecular dynamics simulations of the interaction between the GPCR and a peptide derived from the C terminus of the Gα subunit (Gα peptide) to dissect the molecular mechanisms of G protein selectivity. We observe a direct link between Gα peptide binding and stabilization of the GPCR conformational ensemble. We find that cognate and non-cognate Gα peptides show deep and shallow binding, respectively, and in distinct orientations within the GPCR. Binding of the cognate Gα peptide stabilizes the agonist-bound GPCR conformational ensemble resulting in favorable binding energy and lower flexibility of the agonist-GPCR pair. We identify three hot spot residues (Gαs/Gαq-Gln-384/Leu-349, Gln-390/Glu-355, and Glu-392/Asn-357) that contribute to selective interactions between the β2-adrenergic receptor (β2-AR)-Gαs and V1A receptor (V1AR)-Gαq The Gαs and Gαq peptides adopt different orientations in β2-AR and V1AR, respectively. The β2-AR/Gαs peptide interface is dominated by electrostatic interactions, whereas the V1AR/Gαq peptide interactions are predominantly hydrophobic. Interestingly, our study reveals a role for both favorable and unfavorable interactions in G protein selection. Residue Glu-355 in Gαq prevents this peptide from interacting strongly with β2-AR. Mutagenesis to the Gαs counterpart (E355Q) imparts a cognate-like interaction. Overall, our study highlights the synergy in molecular dynamics and FRET-based approaches to dissect the structural basis of selective G protein interactions.
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