1C84

CRYSTAL STRUCTURE OF PROTEIN TYROSINE PHOSPHATASE 1B COMPLEXED WITH 3-(OXALYL-AMINO)-NAPHTHALENE-2-CARBOXLIC ACID

Summary for 1C84

• Entry DOI: 10.2210/pdb1c84/pdb
• Related: 1C83 1C85 1C86 1C87 1C88 1ECV
• Descriptor: PROTEIN (PROTEIN-TYROSINE PHOSPHATASE 1B), 3-(OXALYL-AMINO)-NAPHTHALENE-2-CARBOXYLIC ACID (3 entities in total)
• Functional Keywords: hydrolase, phosphorylation, ligand, inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Endoplasmic reticulum membrane ; Peripheral membrane protein ; Cytoplasmic side : P18031
• Total number of polymer chains: 1
• Total formula weight: 34979.78

Authors

Andersen, H.S.,Iversen, L.F.,Branner, S.,Rasmussen, H.B.,Moller, N.P. (deposition date: 2000-04-14, release date: 2000-05-03, Last modification date: 2023-12-27)

Primary citation

Andersen, H.S.,Iversen, L.F.,Jeppesen, C.B.,Branner, S.,Norris, K.,Rasmussen, H.B.,Moller, K.B.,Moller, N.P.
2-(oxalylamino)-benzoic acid is a general, competitive inhibitor of protein-tyrosine phosphatases.
J.Biol.Chem., 275:7101-7108, 2000

PubMed Abstract: Protein-tyrosine phosphatases (PTPs) are critically involved in regulation of signal transduction processes. Members of this class of enzymes are considered attractive therapeutic targets in several disease states, e.g. diabetes, cancer, and inflammation. However, most reported PTP inhibitors have been phosphorus-containing compounds, tight binding inhibitors, and/or inhibitors that covalently modify the enzymes. We therefore embarked on identifying a general, reversible, competitive PTP inhibitor that could be used as a common scaffold for lead optimization for specific PTPs. We here report the identification of 2-(oxalylamino)-benzoic acid (OBA) as a classical competitive inhibitor of several PTPs. X-ray crystallography of PTP1B complexed with OBA and related non-phosphate low molecular weight derivatives reveals that the binding mode of these molecules to a large extent mimics that of the natural substrate including hydrogen bonding to the PTP signature motif. In addition, binding of OBA to the active site of PTP1B creates a unique arrangement involving Asp(181), Lys(120), and Tyr(46). PTP inhibitors are essential tools in elucidating the biological function of specific PTPs and they may eventually be developed into selective drug candidates. The unique enzyme kinetic features and the low molecular weight of OBA makes it an ideal starting point for further optimization.

PubMed: 10702277
DOI: 10.1074/jbc.275.10.7101

Experimental method

X-RAY DIFFRACTION (2.35 Å)