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Ligand binding site superposition and comparison based on Atomic Property Fields: identification of distant homologues, convergent evolution and PDB-wide clustering of binding sites.

Totrov M - BMC Bioinformatics (2011)

Bottom Line: A new binding site comparison algorithm using optimal superposition of the continuous pharmacophoric property distributions is reported.Good quality of superposition is also observed on multiple examples.Using the new approach, a measure of site similarity is derived and applied to clustering of ligand binding pockets in PDB.

View Article: PubMed Central - HTML - PubMed

Affiliation: Molsoft LLC,3366 N Torrey Pines Ct, La Jolla, CA 92037, USA. max@molsoft.com

ABSTRACT
A new binding site comparison algorithm using optimal superposition of the continuous pharmacophoric property distributions is reported. The method demonstrates high sensitivity in discovering both, distantly homologous and convergent binding sites. Good quality of superposition is also observed on multiple examples. Using the new approach, a measure of site similarity is derived and applied to clustering of ligand binding pockets in PDB.

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Examples of convergent binding sites on apparently unrelated enzymes, tightly superimposed by APF method: (a) GDP bound to gdp-mannose mannosyl hydrolase (1rya, magenta) and to calcium-dependent endoplasmic reticulum nucleoside diphosphatase (1s1d, green). Residues coordinating guanidyl moiety – the sidechains of K161, W163, Y237 and the backbone of T164 in 1rya align well in space and play the role of R52, F3, and F9 and the backbone of L4 in 1s1d. 1rya belongs to NUDIX hydrolase superfamily and alpha and beta fold class, while 1s1d is classified as apyrase and 5-bladed beta-propeller, according to CDD[27] and SCOP[28]. (b) Binding sites of concanavalin A (1cjp, magenta) and agglutinin (1jot, green). Despite lack of any overall homology, the two proteins bind the central sugar moieties (glucose in concanavalin A complex and galactose in agglutinin complex) of their ligands in a remarkably similar manner: beta-hairpins G98-L99-Y100 (concanavalin A) and G121-Y122-W123 (agglutinin) coordinate O5’ and O6 atoms via backbone hydrogen bonds; Y12 (concavalin A) and Y78 (agglutinin) engage aliphatic carbons on the opposite face of the sugar ring in hydrophobic interactions; D208 and D125 coordinate hydrogens on O4 and O6 hydroxyl oxygens. Parts of ligands other than the central sugar moiety are shown in wire representation for clarity.
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Figure 8: Examples of convergent binding sites on apparently unrelated enzymes, tightly superimposed by APF method: (a) GDP bound to gdp-mannose mannosyl hydrolase (1rya, magenta) and to calcium-dependent endoplasmic reticulum nucleoside diphosphatase (1s1d, green). Residues coordinating guanidyl moiety – the sidechains of K161, W163, Y237 and the backbone of T164 in 1rya align well in space and play the role of R52, F3, and F9 and the backbone of L4 in 1s1d. 1rya belongs to NUDIX hydrolase superfamily and alpha and beta fold class, while 1s1d is classified as apyrase and 5-bladed beta-propeller, according to CDD[27] and SCOP[28]. (b) Binding sites of concanavalin A (1cjp, magenta) and agglutinin (1jot, green). Despite lack of any overall homology, the two proteins bind the central sugar moieties (glucose in concanavalin A complex and galactose in agglutinin complex) of their ligands in a remarkably similar manner: beta-hairpins G98-L99-Y100 (concanavalin A) and G121-Y122-W123 (agglutinin) coordinate O5’ and O6 atoms via backbone hydrogen bonds; Y12 (concavalin A) and Y78 (agglutinin) engage aliphatic carbons on the opposite face of the sugar ring in hydrophobic interactions; D208 and D125 coordinate hydrogens on O4 and O6 hydroxyl oxygens. Parts of ligands other than the central sugar moiety are shown in wire representation for clarity.

Mentions: Perhaps the most intriguing findings are the cases where similar binding mode is observed for the same ligand by two clearly unrelated receptors. APF BSS identified multiple such cases, two of which are illustrated on Figure 8. In both examples, not only similar side chains are lining the pockets, but also the backbone structure locally adopts similar conformation to form structurally convergent binding sites within otherwise unrelated protein folds.


Ligand binding site superposition and comparison based on Atomic Property Fields: identification of distant homologues, convergent evolution and PDB-wide clustering of binding sites.

Totrov M - BMC Bioinformatics (2011)

Examples of convergent binding sites on apparently unrelated enzymes, tightly superimposed by APF method: (a) GDP bound to gdp-mannose mannosyl hydrolase (1rya, magenta) and to calcium-dependent endoplasmic reticulum nucleoside diphosphatase (1s1d, green). Residues coordinating guanidyl moiety – the sidechains of K161, W163, Y237 and the backbone of T164 in 1rya align well in space and play the role of R52, F3, and F9 and the backbone of L4 in 1s1d. 1rya belongs to NUDIX hydrolase superfamily and alpha and beta fold class, while 1s1d is classified as apyrase and 5-bladed beta-propeller, according to CDD[27] and SCOP[28]. (b) Binding sites of concanavalin A (1cjp, magenta) and agglutinin (1jot, green). Despite lack of any overall homology, the two proteins bind the central sugar moieties (glucose in concanavalin A complex and galactose in agglutinin complex) of their ligands in a remarkably similar manner: beta-hairpins G98-L99-Y100 (concanavalin A) and G121-Y122-W123 (agglutinin) coordinate O5’ and O6 atoms via backbone hydrogen bonds; Y12 (concavalin A) and Y78 (agglutinin) engage aliphatic carbons on the opposite face of the sugar ring in hydrophobic interactions; D208 and D125 coordinate hydrogens on O4 and O6 hydroxyl oxygens. Parts of ligands other than the central sugar moiety are shown in wire representation for clarity.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 8: Examples of convergent binding sites on apparently unrelated enzymes, tightly superimposed by APF method: (a) GDP bound to gdp-mannose mannosyl hydrolase (1rya, magenta) and to calcium-dependent endoplasmic reticulum nucleoside diphosphatase (1s1d, green). Residues coordinating guanidyl moiety – the sidechains of K161, W163, Y237 and the backbone of T164 in 1rya align well in space and play the role of R52, F3, and F9 and the backbone of L4 in 1s1d. 1rya belongs to NUDIX hydrolase superfamily and alpha and beta fold class, while 1s1d is classified as apyrase and 5-bladed beta-propeller, according to CDD[27] and SCOP[28]. (b) Binding sites of concanavalin A (1cjp, magenta) and agglutinin (1jot, green). Despite lack of any overall homology, the two proteins bind the central sugar moieties (glucose in concanavalin A complex and galactose in agglutinin complex) of their ligands in a remarkably similar manner: beta-hairpins G98-L99-Y100 (concanavalin A) and G121-Y122-W123 (agglutinin) coordinate O5’ and O6 atoms via backbone hydrogen bonds; Y12 (concavalin A) and Y78 (agglutinin) engage aliphatic carbons on the opposite face of the sugar ring in hydrophobic interactions; D208 and D125 coordinate hydrogens on O4 and O6 hydroxyl oxygens. Parts of ligands other than the central sugar moiety are shown in wire representation for clarity.
Mentions: Perhaps the most intriguing findings are the cases where similar binding mode is observed for the same ligand by two clearly unrelated receptors. APF BSS identified multiple such cases, two of which are illustrated on Figure 8. In both examples, not only similar side chains are lining the pockets, but also the backbone structure locally adopts similar conformation to form structurally convergent binding sites within otherwise unrelated protein folds.

Bottom Line: A new binding site comparison algorithm using optimal superposition of the continuous pharmacophoric property distributions is reported.Good quality of superposition is also observed on multiple examples.Using the new approach, a measure of site similarity is derived and applied to clustering of ligand binding pockets in PDB.

View Article: PubMed Central - HTML - PubMed

Affiliation: Molsoft LLC,3366 N Torrey Pines Ct, La Jolla, CA 92037, USA. max@molsoft.com

ABSTRACT
A new binding site comparison algorithm using optimal superposition of the continuous pharmacophoric property distributions is reported. The method demonstrates high sensitivity in discovering both, distantly homologous and convergent binding sites. Good quality of superposition is also observed on multiple examples. Using the new approach, a measure of site similarity is derived and applied to clustering of ligand binding pockets in PDB.

Show MeSH