Selectivity determinants of GPCR–G-protein binding
Open accessAbstract
The selective coupling of G-protein-coupled receptors (GPCRs) to specific G proteins is critical to trigger the appropriate physiological response. However, the determinants of selective binding have remained elusive. Here we reveal the existence of a selectivity barcode (that is, patterns of amino acids) on each of the 16 human G proteins that is recognized by distinct regions on the approximately 800 human receptors. Although universally conserved positions in the barcode allow the receptors to bind and activate G proteins in a similar manner, different receptors recognize the unique positions of the G-protein barcode through distinct residues, like multiple keys (receptors) opening the same lock (G protein) using non-identical cuts. Considering the evolutionary history of GPCRs allows the identification of these selectivity-determining residues. These findings lay the foundation for understanding the molecular basis of coupling selectivity within individual receptors and G proteins.
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The protein-protein interactions that propagate the intracellular signal often allosterically trigger post-translational modifications (PTMs).
“Furthermore, the protein–protein interactions that propagate the intracellular signal often allosterically trigger post-translational modifications (PTMs) [30].”
From Intrinsically disordered proteins play diverse roles in cell signaling (2022) · cites this paper as [30]
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- Authors
- Flock, T., Hauser, A. S., Lund, N., Gloriam, D. E., Balaji, S., & Babu, M. M.
- Affiliations
- MRC Laboratory of Molecular Biology (GB)
- University of Copenhagen (DK)
- Corresponding author
- Flock, Tilman
- Babu, M. Madan
- Venue
- Nature
- Published
- 2017-05
- Volume
- 545
- Issue
- 7654
- Pages
- 317-322
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5846738
- OpenAlex
- W2613102394
- Cited by
- 384
- References
- 63
- Citations by year
- 2026: 27 · 2025: 36 · 2024: 34 · 2023: 36 · 2022: 44 · 2021: 49 · 2020: 47 · 2019: 50 · 2018: 47 · 2017: 14
- FWCI
- 17.77
- Type
- journal article
- Language
- en
- Open access
- Licence
- other-oa
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Lister Institute of Preventive Medicine
- Lundbeckfonden (R163-2013-16327)
- H. Lundbeck A/S
- Medical Research Council (MC_U105185859)
- Fitzwilliam College, University of Cambridge
- H2020 European Research Council (639125)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- G protein-coupled receptors, Gα proteins, receptor-G protein interaction, G protein-coupled receptor signaling
- MeSH terms
- Amino Acid Sequence, Binding Sites, Humans, Models, Molecular, Protein Binding, Protein Conformation, Substrate Specificity, User-Computer Interface, Evolution, Molecular, Internet, Heterotrimeric GTP-Binding Proteins, Receptors, G-Protein-Coupled
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