PDBsum entry 1c88

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Hydrolase PDB id
Protein chain
297 a.a. *
Waters ×225
* Residue conservation analysis

References listed in PDB file
Key reference
Title Structure-Based design of a low molecular weight, Nonphosphorus, Nonpeptide, And highly selective inhibitor of protein-Tyrosine phosphatase 1b.
Authors L.F.Iversen, H.S.Andersen, S.Branner, S.B.Mortensen, G.H.Peters, K.Norris, O.H.Olsen, C.B.Jeppesen, B.F.Lundt, W.Ripka, K.B.Møller, N.P.Møller.
Ref. J Biol Chem, 2000, 275, 10300-10307. [DOI no: 10.1074/jbc.275.14.10300]
PubMed id 10744717
Several protein-tyrosine phosphatases (PTPs) have been proposed to act as negative regulators of insulin signaling. Recent studies have shown increased insulin sensitivity and resistance to obesity in PTP1B knockout mice, thus pointing to this enzyme as a potential drug target in diabetes. Structure-based design, guided by PTP mutants and x-ray protein crystallography, was used to optimize a relatively weak, nonphosphorus, nonpeptide general PTP inhibitor (2-(oxalyl-amino)-benzoic acid) into a highly selective PTP1B inhibitor. This was achieved by addressing residue 48 as a selectivity determining residue. By introducing a basic nitrogen in the core structure of the inhibitor, a salt bridge was formed to Asp-48 in PTP1B. In contrast, the basic nitrogen causes repulsion in other PTPs containing an asparagine in the equivalent position resulting in a remarkable selectivity for PTP1B. Importantly, this was accomplished while retaining the molecular weight of the inhibitor below 300 g/mol.
Figure 1.
Fig. 1. Chemical structures of OBA-1 and its derivatives.
Figure 4.
Fig. 4. Schematic representation of compound 5 in the active site pocket of PTP1B. Distances are in Å for noncovalent interactions between PTP1B and compound 5. Van der Waals interactions are illustrated by arcs. Nomenclature used for the different groups of compound 5.
The above figures are reprinted by permission from the ASBMB: J Biol Chem (2000, 275, 10300-10307) copyright 2000.
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