Hot topic: Selectivity determinants of GPCR–G-protein binding

As a detailed comparative sequence/structure/evolution analysis it is relatively unusual (in a good sense) to see such a bioinformatics article in Nature. This tour de force was a collaboration between MRC Laboratory of Molecular Biology, Cambridge UK and the Department of Drug Design and Pharmacology, University of Copenhagen (home of the GPCRdb team). As we know, GPCR signal transduction involves the binding of ligand-activated receptors to their appropriate Gα proteins. In this work selectivity-determining positions for signal transduction (as structural “barcodes”) were inferred by comprehensively comparing the sequence conservation between paralogues and orthologues, incorporating information from recent structures. The residue positions for the interaction interfaces are collated and presented at gpcrdb.org (tab ‘Signal Proteins’) for all human receptors and their 16 Gα proteins. This will be updated (including data from new structures) as a guide to interface determinants of coupling selectivity. Many applications of this resource can be envisaged. These could include: exploring options to target GPCR-G protein interfaces with agents that block coupling between the receptor and G protein intracellularly, protein engineering, structural studies and understanding the consequences of natural variation or rare disease associated mutations occurring in the vicinity of the barcode positions.

Note that all GtoPdb GPCRs have cross-references to GPCRdb (who we collaborate with) so users can navigate structural data (including the barcode positions) via GPCRdb, but also exploit ligand-centric navigation via GtoPdb and links out to genomic variants via the Ensembl links.

[1] Flock et al. (2017). Selectivity determinants of GPCR-G-protein binding. Nature, 545: 317-322. [PMID:28489817].

Comments by by Chris Southan (@cdsouthan)