GPCRdb in 2018: adding GPCR structure models and ligands.

Gáspár Pándy-Szekeres,Alexander S Hauser,Kasper Harpsøe,Stefan Mordalski,Andrzej J Bojarski,Tsonko M Tsonkov,David E Gloriam,Christian Munk

doi:10.1093/nar/gkx1109

Gáspár Pándy-Szekeres, Alexander S Hauser + Show 6 more

Open Access

https://doi.org/10.1093/nar/gkx1109

Copy DOI

Abstract

G protein-coupled receptors are the most abundant mediators of both human signalling processes and therapeutic effects. Herein, we report GPCRome-wide homology models of unprecedented quality, and roughly 150 000 GPCR ligands with data on biological activities and commercial availability. Based on the strategy of ‘Less model – more Xtal’, each model exploits both a main template and alternative local templates. This achieved higher similarity to new structures than any of the existing resources, and refined crystal structures with missing or distorted regions. Models are provided for inactive, intermediate and active states—except for classes C and F that so far only have inactive templates. The ligand database has separate browsers for: (i) target selection by receptor, family or class, (ii) ligand filtering based on cross-experiment activities (min, max and mean) or chemical properties, (iii) ligand source data and (iv) commercial availability. SMILES structures and activity spreadsheets can be downloaded for further processing. Furthermore, three recent landmark publications on GPCR drugs, G protein selectivity and genetic variants have been accompanied with resources that now let readers view and analyse the findings themselves in GPCRdb. Altogether, this update will enable scientific investigation for the wider GPCR community. GPCRdb is available at http://www.gpcrdb.org.

Highlights

G protein-coupled receptors represent both the largest membrane and drug target protein families, accounting for 800 (4%) human genes and 34% of FDA-approved drug targets [1]
Structural biology and pharmacology breakthroughs have opened up new GPCR research fields exploring structural mechanisms and complexes, and novel principles to achieve a more selective action through ‘biased agonism’ preferentially activating a specific signal protein or ‘allosteric modulation’ of the natural ligand response from an alternative binding site
We present a new GPCR ligand resource that applies the same quality requirements as Guide to PHARMACOLOGY, but encompasses ligands from ChEMBL, GLIDA and the PDSP Ki database

Summary

Introduction

G protein-coupled receptors represent both the largest membrane and drug target protein families, accounting for 800 (4%) human genes and 34% of FDA-approved drug targets [1]. All GPCRs share a common heptahelical transmembrane domain carrying the signal from the extracellular ligand to the intracellular signalling protein, typically one of four families of G proteins or ␤arrestin, which can internalise the receptor. Structural biology and pharmacology breakthroughs have opened up new GPCR research fields exploring structural mechanisms and complexes, and novel principles to achieve a more selective action through ‘biased agonism’ preferentially activating a specific signal protein or ‘allosteric modulation’ of the natural ligand response from an alternative binding site. Current data ranges all 398 human non-olfactory GPCRs and 16 G proteins, over 14 000 species orthologues, 30 328 binding site mutations, all 218 experimental structures, and 10 059 extracted ligand interactions

Methods

Results

Conclusion