Integrating structural and mutagenesis data to elucidate GPCR ligand binding

By Christian Munk, Kasper Harpsøe, Alexander Sebastian Hauser, Vignir Ísberg, David E. Gloriam. 2016

56 citations recorded by the source corpus.

G protein-coupled receptors (GPCRs) represent the largest family of human membrane proteins, as well as drug targets. A recent boom in GPCR structural biology has provided detailed images of receptor ligand binding sites and interactions on the molecular level. An ever-increasing number of ligands is reported that exhibit activity through multiple receptors, binding in allosteric sites, and bias towards different intracellular signalling pathways. Furthermore, a wealth of single point mutants has accumulated in literature and public databases. Integrating these structural and mutagenesis data will help elucidate new GPCR ligand binding sites, and ultimately design drugs with tailored pharmacological activity.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology

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Citations in the corpus

GPCRdb in 2021: integrating GPCR sequence, structure and function (2020, methodology): “Furthermore, GPCRdb has data driven tools to identify sequence signatures of functional residue determinants (see below), to mutate ligand binding sites (27) and to design constructs and experiments for structure determination (12).”
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 .”
GPCRdb in 2023: state-specific structure models using AlphaFold2 and new ligand resources (2022, methodology): “Data-driven experiment design tools: The current set of data-driven tools serve to (i) design constructs for crystallography/cryo-EM studies (28), (ii) identify functional determinants from comparative sequence analysis, (iii) provide mutations stabilizing inactive/active states, and mutate ligand b”
Pharmacogenomics of GPCR Drug Targets (2018, unknown): “For instance, of the 108 GPCR drug targets, we ﬁnd that for 67 receptors, there is at least one allele with a mutation in the highly conserved 3.50 3 50 position (GPCRdb numbering) and for 41 receptors in the position 8.49 3 49.”