GPCRdb in 2018: adding GPCR structure models and ligands

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.

Receptor selectivity between the G proteins Gα 12 and Gα 13 is defined by a single leucine‐to‐isoleucine variation

“…A ) The C‐terminal 27 aa of Gα 12 and Gα 13 are shown with amino acids that differ within the last 10 aa boxed. B ) The Common Gα Numbering system (36, 37) is used to highlight these differences and their positions within the C‐terminal G protein α5 helix. C, D ) hGPR35‐SPASM sensors were constructed in which residues at positions G.H5.17 and G.H5.18 ( C ) or G.H5.22 and G.H5.23 ( D ) were swapped between Gα 12 and Gα 13 .…”

“…(36). Structure‐based sequence alignments were performed using the GPCR Database numbering for GPCRs and the Common Gα Numbering scheme for G proteins (36,37). In this scheme, G is the G protein, H5 is the α5 helix, and the numerical value is the position from the start of that helix ( e.g ., residue 23), hence G. H5.23.…”

“…We first investigated sequence-based selectivity determinants in Ga 13 by evolutionary conservation for G.H5.23 with its orthologs and paralogs as previously described in Flock et al (36). Structure-based sequence alignments were performed using the GPCR Database numbering for GPCRs and the Common Ga Numbering scheme for G proteins (36,37). In this scheme, G is the G protein, H5 is the a5 helix, and the numerical value is the position from the start of that helix (e.g., residue 23), hence G.H5.23.…”

Uterine Gα q/11 signaling, in a progesterone‐dependent manner, critically regulates the acquisition of uterine receptivity in the female mouse

“…These are leucine-rich repeat-containing GPCR 4 (LGR4) (9)(10)(11), lysophosphatidic acid receptor 3 (LPAR3) (12), and the kisspeptin receptor (KISS1R) (13)(14)(15)). LGR4 appears to couple to Ga s, LPAR3 couples to Ga q/11 and Ga i/0 (16), and KISS1R couples to Ga q/11 (16,17). Deletion of epithelial LGR4 in the mouse results in reduced endometrial gland formation (adenogenesis), persistent epithelial E2 receptor a signaling, P4 resistance, and a lack of decidualization (9)(10)(11).…”

PAC1 Receptors: Shapeshifters in Motion

“…Among the nearly 700 members of the class A receptors, including the β-adrenergic, muscarinic, serotoninergic, dopaminergic and purinergic receptors, the structures of approximately 32 receptors have been solved from crystallography studies (Zhang et al 2015; Pándy-Szekeres et al 2018). Perhaps not surprisingly, nearly 40% of all pharmaceutical drugs target class A receptors (Luttrell et al 2015; Zhang et al 2015).…”