Classification of Binding Site Conformations of Protein Tyrosine Phosphatase 1B

Abstract

Hundred and two binding sites from 91 Protein Data Bank files for protein tyrosine phosphatase 1B with different ligands have been compared. It was found that they can be divided into five clusters. Additional clusters were formed by the unliganded and oxidized enzyme. The centroids of the clusters can be used as starting points for further studies of enzyme-inhibitor interaction by computer simulations. A special software tool has been created for the investigation of protein tyrosine phosphatase 1B and other enzymes. It performs multiple comparisons of selected parts of Protein Data Bank files, as well as further clustering, and determines mobility of separate residues.Key words: binding sites, clustering, conformations, docking, protein tyrosine phosphatase 1B, structure similarity Received 10 December 2010, revised 10 February 2012 and accepted for publication 25 February 2012 Protein tyrosine phosphatases regulate a number of biochemical processes governed by dephosphorylation of phosphotyrosine residues in proteins, including cell-signaling and metabolism pathways (1-3). Intracellular protein tyrosine phosphatase 1B (PTP1B) is known to be implicated in insulin receptor dephosphorylation and considered a negative regulator of insulin signal transduction (4). Therefore, PTP1B is one of the most promising therapeutic targets for potential treatment of type 2 diabetes and obesity (5). There is growing interest in developing potent and selective inhibitors of this enzyme (2,6). Derivatives of carboxylic, phosphonic, sulfonic acids (7-10), heterocyclic, and other compounds (11,12) have been identified as PTP1B inhibitors. Several active compounds have been studied using computer-based approaches, including molecular docking (13,14). Docking results were also used to understand detailed mechanisms of inhibitor binding to the enzyme (15-19).Structurally important regions of PTP1B for inhibitor binding are known (20) to be active site residues (His214-Arg221, P-loop), WPD loop (Thr177-Pro185), substrate recognition loop (Lys36, Val49, Lys120), and secondary binding site (Tyr20, Arg24, His25, Ala27, Phe52, Arg254, Met258, Gly259) (Figure 1). X-ray crystallographic analysis of PTP1B complexed with different ligand reveals significant differences in the conformation of binding sites of the enzyme. For example, many crystal structures of PTP1B, which are available in the Protein Data Bank (PDB), have WPD loop closed onto an inhibitor (21,22). In contrast, the X-ray crystal structures of PTP1B complexed with other ligands indicate that WPD loop can remain open (23,24). Studies of aryl diketoacid derivatives showed that these compounds bind PTP1B in the catalytically inactive, WPD loop opening conformation, and targeting the WPD loop open form leads to non-competitive inhibition of the enzyme activity (23). Thus, the conformational changes of WPD loop of PTP1B may be crucial for inhibitor binding and should be taken into account in computer modeling the enzyme-inhibitor interactions.Our goal in this work was to classi...

Structural analysis of protein tyrosine phosphatase 1B reveals potentially druggable allosteric binding sites

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Testing of a new docking scoring function on the example of inhibitors of protein tyrosine phosphatase 1B

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Calix[4]arene α-hydroxymethylphosphonic acids as potential inhibitors of protein tyrosine phosphatases

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