Selectivity determinants of GPCR-G protein binding

By T. Flock, Alexander Sebastian Hauser, N. Lund, David E. Gloriam, S. Balaji, M. M. Babu. 2017

336 citations recorded by the source corpus.

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.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cellular and Molecular Neuroscience

In Molecular Biology

Citations in the corpus

GPCRdb in 2021: integrating GPCR sequence, structure and function (2020, background): “The published (26) parts of the G protein section of GPCRdb features G protein sequence alignments, snakelike residue topology diagrams, intersection or dissection of receptors based on their coupling to the four main G protein families and in vitro GPCR and G protein mutations/chimeras with effect ”
An Online Resource for GPCR Structure Determination and Analysis (2019, methodology): “The analysis can then be extended through the integrated tools for druggable binding sites 16–18 and G protein interfaces 19 .”
Structures of signaling complexes of lipid receptors S1PR1 and S1PR5 reveal mechanisms of activation and drug recognition (2021, background): “Differences in sequence and conformation are observed in the ICL2 region of S1PRs, which indicates that ICL2 may play versatile roles in either receptor activation or G protein selectivity.(42)”
Pharmacogenomics of GPCR Drug Targets (2018, neutral): “…by affecting allosteric sites, effector selectivity sites, receptor stability, and oligomerization (Congreve et al., 2017; Costa-Neto et al., 2016; Flock et al., 2015, 2017; Gahbauer Cell 172 , 41–54, January 11, 2018 43 and Bo¨ckmann, 2016; Katritch et al., 2014; Venkatakrishnan et al., 2013,…”
GPCRdb in 2018: adding GPCR structure models and ligands (2017, background): “In the last two years, GPCRdb has enabled and disseminated high-impact biological analyses (1,19,20), through resources that also allow scientists to analyse the data themselves.”