ABSTRACT
Protein tyrosine phosphatase 1B (PTP1B) is a prototype non receptor cytoplasmic PTPase enzyme that has been implicated in regulation of insulin and leptin signaling pathways. Studies on PTP1B knockout mice and PTP1B antisense treated mice suggested that inhibition of PTP1B would be an effective strategy for the treatment of type II diabetes and obesity. Here we report the X-ray structure of PTP1B in complex with compound IN1834-146C (PDB ID 4I8N). The crystals belong to P3121 space group with cell dimensions (a = b = 87.89 Å, c = 103.68 Å) diffracted to 2.5 Å. The crystal structure contained one molecule of protein in the asymmetric unit and was solved by molecular replacement method. The compound engages both catalytic site and allosteric sites of PTP1B protein. We described the molecular interaction of the compound with the active site residues of PTP1B in this crystal structure report.
Subject(s)
Binding Sites/drug effects , Catalytic Domain/drug effects , Protein Tyrosine Phosphatase, Non-Receptor Type 1/antagonists & inhibitors , Protein Tyrosine Phosphatase, Non-Receptor Type 1/ultrastructure , Animals , Cloning, Molecular , Crystallography, X-Ray , Diabetes Mellitus, Type 2/therapy , Mice , Mice, Knockout , Obesity/therapy , Protein Tyrosine Phosphatase, Non-Receptor Type 1/geneticsABSTRACT
Even though protein tyrosine phosphatase has been identified as a validated therapeutic target over a decade for type II diabetes and obesity, developing a selective inhibitor to protein tyrosine phosphatase 1B (PTP1B) over other cellular PTPases has been a complicated task owing to the highly conserved and polar nature of the PTP1B catalytic site. Virtual screening study of in-house chemical depository resulted in the prioritization of few low molecular weight compounds as PTP1B inhibitors. The in-vitro pNPP assays were carried out on prioritized compounds in both PTP1B and T-cell protein tyrosine phosphatase (TCPTP). From this we identified four low molecular weight compounds as PTP1B inhibitors, of which the compound AU-2439 has shown 5 fold selectivity towards PTP1B over highly homologous TCPTP. In this short communication selectivity of AU-2439 is explained based on interaction with critical active site residues in both proteins using docking models.
Subject(s)
Enzyme Inhibitors/chemistry , Protein Tyrosine Phosphatase, Non-Receptor Type 1/antagonists & inhibitors , Protein Tyrosine Phosphatase, Non-Receptor Type 2/antagonists & inhibitors , Binding Sites , Catalytic Domain , Enzyme Inhibitors/metabolism , Humans , Molecular Docking Simulation , Protein Binding , Protein Tyrosine Phosphatase, Non-Receptor Type 1/genetics , Protein Tyrosine Phosphatase, Non-Receptor Type 1/metabolism , Protein Tyrosine Phosphatase, Non-Receptor Type 2/genetics , Protein Tyrosine Phosphatase, Non-Receptor Type 2/metabolism , Recombinant Proteins/biosynthesis , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Thiazolidinediones/chemistryABSTRACT
We have identified a novel 7-azaindole series of anaplastic lymphoma kinase (ALK) inhibitors. Compounds 7b, 7 m and 7 n demonstrate excellent potencies in biochemical and cellular assays. X-ray crystal structure of one of the compounds (7 k) revealed a unique binding mode with the benzyl group occupying the back pocket, explaining its potency towards ALK and selectivity over tested kinases particularly Aurora-A. This binding mode is in contrast to that of known ALK inhibitors such as Crizotinib and NVP-TAE684 which occupy the ribose binding pocket, close to DFG motif.
