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.

G protein-coupled receptors (GPCRs) form both the largest family of membrane proteins and drug targets, mediating the action of one-third of medicines. The GPCR database, GPCRdb serves >4 000 researchers every month and offers reference data, analysis of own or literature data, experiment design and dissemination of published datasets. Here, we describe new and updated GPCRdb resources with a particular focus on integration of sequence, structure and function. GPCRdb contains all human non-olfactory GPCRs (and >27 000 orthologs), G-proteins and arrestins. It includes over 2 000 drug and in-trial agents and nearly 200 000 ligands with activity and availability data. GPCRdb annotates all published GPCR structures (updated monthly), which are also offered in a refined version (with re-modeled missing/distorted regions and reverted mutations) and provides structure models of all human non-olfactory receptors in inactive, intermediate and active states. Mutagenesis data in the GPCRdb spans natural genetic variants, GPCR-G protein interfaces, ligand sites and thermostabilising mutations. A new sequence signature tool for identification of functional residue determinants has been added and two data driven tools to design ligand site mutations and constructs for structure determination have been updated extending their coverage of receptors and modifications. The GPCRdb is available at https://gpcrdb.org.

G protein-coupled receptors (GPCRs) are involved in numerous physiological processes and are the most frequent targets of approved drugs. The explosion in the number of new 3D molecular structures of GPCRs (3D-GPCRome) during the last decade has greatly advanced the mechanistic understanding and drug design opportunities for this protein family. Molecular dynamics (MD) simulations have become a widely established technique to explore the conformational landscape of proteins at an atomic level. However, the analysis and visualization of MD simulations require efficient storage resources and specialized software. Here we present GPCRmd (http://gpcrmd.org/), an online platform that incorporates web-based visualization capabilities as well as a comprehensive and user-friendly analysis toolbox that allows scientists from different disciplines to visualize, analyse and share GPCR MD data.GPCRmd originates from a community-driven effort to create the first open, interactive, and standardized database of GPCR MD simulations.However, static high-resolution structures provide little information on the intrinsic 71 flexibility of GPCRs, a key aspect to fully understand their function. Important advances 72

G protein-coupled receptors (GPCRs) are divided phylogenetically into six classes, A-F 1 , 2 . Over 370 structures of vertebrate GPCRs (classes A, B, C and F) have been determined, leading to a substantial understanding of their function 3 . In contrast, there are no structures of Class D GPCRs, which are found exclusively in fungi where they regulate survival and reproduction. We have determined the first structure of a family D GPCR, the Saccharomyces cerevisiae pheromone receptor Ste2, in an active state coupled to the heterotrimeric G protein Gpa1-Ste4-Ste18. Ste2 was purified as a homodimer that coupled to two G proteins. The dimer interface of Ste2 is formed by the N-terminus, transmembrane helices H1, H2, H7 and the first extracellular loop ECL1. We established a Class D1 generic residue numbering system (CD1) to enable comparisons with orthologues and other GPCR classes. The structure of Ste2 bears similarities in overall topology to Class A GPCRs, but H4 is shifted by over 20 Å and the G protein binding site is a shallow groove rather than a cleft. The structure provides a template for the design of novel drugs targeting fungal GPCRs that could be utilised to treat a number of intractable fungal diseases 4 .

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.

Two-thirds of signaling substances, several sensory stimuli and over one-third of drugs act via receptors coupling to G proteins. Here, we present an online platform for G protein research with reference data and tools for analysis, visualization and design of scientific studies across disciplines and areas. This platform may help translate new pharmacological, structural and genomic data into insights on G protein signaling vital for human physiology and medicine. The G protein database is accessible at https://gproteindb.org.

G protein-coupled receptors (GPCRs) are involved in numerous physiological processes and the most frequent targets of approved drugs. The striking explosion in the number of new 3D molecular structures of GPCRs (3D-GPCRome) during the last decade has greatly advanced the mechanistic understanding and drug design opportunities for this protein family. While experimentally-resolved structures undoubtedly provide valuable snapshots of specific GPCR conformational states, they give only limited information on their flexibility and dynamics associated with function.Molecular dynamics (MD) simulations have become a widely established technique to explore the conformational landscape of proteins at an atomic level. However, the analysis and visualization of MD simulations requires efficient storage resources and specialized software, hence limiting the dissemination of these data to specialists in the field. Here we present the GPCRmd, an online platform with web-based visualization capabilities and a comprehensive analysis toolbox that allows scientists from any discipline to visualize, share, and analyse GPCR MD data. We describe the GPCRmd in the context of a community-driven effort to create the first open, interactive, and standardized database of GPCR MD simulations. We demonstrate the power of this resource by performing comparative analyses of multiple GPCR simulations on two mechanisms critical to receptor function: internal water networks and sodium ion interaction.

Receptor function is traditionally controlled from the orthosteric binding site of G-protein coupled receptors. Here, we show that the functional activity and signalling of human dopamine D2 and D3 receptor...