FireDB: a compendium of biological and pharmacologically relevant ligands

Abstract

FireDB (http://firedb.bioinfo.cnio.es) is a curated inventory of catalytic and biologically relevant small ligand-binding residues culled from the protein structures in the Protein Data Bank. Here we present the important new additions since the publication of FireDB in 2007. The database now contains an extensive list of manually curated biologically relevant compounds. Biologically relevant compounds are informative because of their role in protein function, but they are only a small fraction of the entire ligand set. For the remaining ligands, the FireDB provides cross-references to the annotations from publicly available biological, chemical and pharmacological compound databases. FireDB now has external references for 95% of contacting small ligands, making FireDB a more complete database and providing the scientific community with easy access to the pharmacological annotations of PDB ligands. In addition to the manual curation of ligands, FireDB also provides insights into the biological relevance of individual binding sites. Here, biological relevance is calculated from the multiple sequence alignments of related binding sites that are generated from all-against-all comparison of each FireDB binding site. The database can be accessed by RESTful web services and is available for download via MySQL.

Figure 1.

Biological and non-biological binding of sucrose. (A) sucrose-binding site of a bacterial levan fructotransferase (PDB: 4FFH). This site is described in the associated paper as biological and sucrose is the substrate. FireDB annotations for the ligands in the collapsed MSS are shown in the upper right panel. ‘E’ represents the number of evolutionarily related sites found in FireDB and the percentage shows the occupancy, calculated from the number of chains in the MSS that bind ligands at this site (in this case 2 of 16 chains). (B) sucrose-binding site of a bacterial tRNA-splicing ligase (PDB: 4DWR). This site is not biological, and sucrose is cited as part of the crystallization mix in the related paper. The FireDB data for this MSS shows that the occupancy is high (9 of 11 chains) but there are no homologous sites (E = 0). (C) Clicking on the ‘E = 8’ icon in (A) will lead the user to the alignment of evolutionarily related sites for the levan fructotransferase-binding site (4FFH). Residues in the binding site alignment are coloured: the darker is the blue, the more conserved the position. Much of the site is conserved even in distant homologous sites and the nature of the bound ligands (Ligand Compounds) suggests that this is a biologically important sugar-binding site.

Figure 2.

A screen capture from the new ligand information web pages in FireDB. The user can directly query the database using the PDB ligand three-letter code or can search using a keyword. Searches with keywords generate a window with the result of the search (right). Information is shown in pull-down tabs. General information is shown in the summary tab, and an additional three tabs are generated when information is available. The external references tab appears when a match with an external database has been found; a manual references tab is generated if manual annotation has been collected from the literature.