PoSSuM: a database of similar protein-ligand binding and putative pockets

Abstract

Numerous potential ligand-binding sites are available today, along with hundreds of thousands of known binding sites observed in the PDB. Exhaustive similarity search for such vastly numerous binding site pairs is useful to predict protein functions and to enable rapid screening of target proteins for drug design. Existing databases of ligand-binding sites offer databases of limited scale. For example, SitesBase covers only ~33,000 known binding sites. Inferring protein function and drug discovery purposes, however, demands a much more comprehensive database including known and putative-binding sites. Using a novel algorithm, we conducted a large-scale all-pairs similarity search for 1.8 million known and potential binding sites in the PDB, and discovered over 14 million similar pairs of binding sites. Here, we present the results as a relational database Pocket Similarity Search using Multiple-sketches (PoSSuM) including all the discovered pairs with annotations of various types. PoSSuM enables rapid exploration of similar binding sites among structures with different global folds as well as similar ones. Moreover, PoSSuM is useful for predicting the binding ligand for unbound structures, which provides important clues for characterizing protein structures with unclear functions. The PoSSuM database is freely available at http://possum.cbrc.jp/PoSSuM/.

Figure 1.

Categorization of 14 million obtained pairs. (A) 9 625 132 pairs (66%) comprised only known ligand-binding sites, whereas 4 930 925 pairs (34%) comprised a known ligand-binding site and a putative site. (B) Undefined pairs were 7 042 317 (49%). The remaining pairs were categorized into two groups: 5 540 245 pairs of homologs (38%) and 1 973 495 pairs of analogs (13%).

Figure 2.

Submission form of PoSSuM. PDB ID and HET code of ligand should be specified for SearchK; PDB ID is required for SearchP.

Figure 3.

Result report of PoSSuM. Blue and green rows, respectively, show the known ligand-binding sites and putative sites.

Figure 4.

Color scheme for the superposed binding sites. Pink and cyan colored sticks, respectively, show the binding site of query and hit. The red sticks show a ligand of the query site (i.e. user-specified on the submit form).

Figure 5.

Superposition of a query site to a hit. (A) Superposition of a BIR-binding site of 1R1H (pink and red) a TI1-binding site of 1QF1 (cyan and green). Orange shows the conserved catalytic residues for both sites. (B) Superposition of a putative site of 3K0B (pink) and a SAH-binding site of 2ORE (cyan and green).