GPCRdb in 2023: state-specific structure models using AlphaFold2 and new ligand resources

Abstract

G protein-coupled receptors (GPCRs) are physiologically abundant signaling hubs routing hundreds of extracellular signal substances and drugs into intracellular pathways. The GPCR database, GPCRdb supports >5000 interdisciplinary researchers every month with reference data, analysis, visualization, experiment design and dissemination. Here, we present our fifth major GPCRdb release setting out with an overview of the many resources for receptor sequences, structures, and ligands. This includes recently published additions of class D generic residue numbers, a comparative structure analysis tool to identify functional determinants, trees clustering GPCR structures by 3D conformation, and mutations stabilizing inactive/active states. We provide new state-specific structure models of all human non-olfactory GPCRs built using AlphaFold2-MultiState. We also provide a new resource of endogenous ligands along with a larger number of surrogate ligands with bioactivity, vendor, and physiochemical descriptor data. The one-stop-shop ligand resources integrate ligands/data from the ChEMBL, Guide to Pharmacology, PDSP Ki and PubChem database. The GPCRdb is available at https://gpcrdb.org.

Figure 1.

GPCR data, analysis resources and data-driven experiment tools in the GPCRdb 2023 release. The numbers to the left of each menu item are publication references with more information (including 30–32).

Figure 2.

Drug/ligand data, analysis, data-driven experiment tool, and data deposition in the GPCRdb 2023 release. The numbers to the left of each menu item are publication references with more information.

Figure 3.

Structure models of the histamine H₂ and serotonin 5-HT_5A receptors in both the active and inactive states built with AlphaFold-Multistate.

Figure 4.

Ligand info page. The Ligands subsection of GPCRdb has been extended to 211 320 ligands and 466 278 binding affinity or potency values from the ChEMBL (16), Guide to Pharmacology (15) or PDSP K_i databases (https://pdsp.unc.edu/databases/kidb.php). The new ligand info page shows ligand structure, names, chemical properties, molecule type, drug status, and endogenous/surrogate status, and database links. When available, GPCR-ligand crystal/cryo-EM structure complexes and mutations affecting ligand activity are also shown. Bioactivities across receptor targets are shown in the browser at the bottom.

Figure 5.

The endogenous ligand resource offers browsing across both multiple ligand and receptors. Four sections present (i) receptors (names and classification), (ii) endogenous ligands (name with link to detailed ligand info, ligand type (small molecule, peptide, protein), classification into principal, secondary or none categories, and potency rank), (iii) bioactivities (pEC₅₀ and pK_i minimum, average, and maximum values across studies) and (iv) references (publication link). All endogenous ligands and their primary/secondary classification were derived from the Guide to Pharmacology database (15).