1c84: Difference between revisions
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|PDB= 1c84 |SIZE=350|CAPTION= <scene name='initialview01'>1c84</scene>, resolution 2.35Å | |PDB= 1c84 |SIZE=350|CAPTION= <scene name='initialview01'>1c84</scene>, resolution 2.35Å | ||
|SITE= | |SITE= | ||
|LIGAND= <scene name='pdbligand=761:3-(OXALYL-AMINO)-NAPHTHALENE-2-CARBOXYLIC ACID'>761</scene> | |LIGAND= <scene name='pdbligand=761:3-(OXALYL-AMINO)-NAPHTHALENE-2-CARBOXYLIC+ACID'>761</scene> | ||
|ACTIVITY= [http://en.wikipedia.org/wiki/Protein-tyrosine-phosphatase Protein-tyrosine-phosphatase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.3.48 3.1.3.48] | |ACTIVITY= <span class='plainlinks'>[http://en.wikipedia.org/wiki/Protein-tyrosine-phosphatase Protein-tyrosine-phosphatase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.3.48 3.1.3.48] </span> | ||
|GENE= | |GENE= | ||
|DOMAIN= | |||
|RELATEDENTRY=[[1ecv|1ECV]], [[1c83|1C83]], [[1c85|1C85]], [[1c86|1C86]], [[1c87|1C87]], [[1c88|1C88]] | |||
|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1c84 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1c84 OCA], [http://www.ebi.ac.uk/pdbsum/1c84 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1c84 RCSB]</span> | |||
}} | }} | ||
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==Overview== | ==Overview== | ||
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. | 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. | ||
==About this Structure== | ==About this Structure== | ||
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[[Category: Moller, N P.]] | [[Category: Moller, N P.]] | ||
[[Category: Rasmussen, H B.]] | [[Category: Rasmussen, H B.]] | ||
[[Category: hydrolase]] | [[Category: hydrolase]] | ||
[[Category: inhibitor]] | [[Category: inhibitor]] | ||
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[[Category: phosphorylation]] | [[Category: phosphorylation]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 30 19:16:29 2008'' | ||
Revision as of 19:16, 30 March 2008
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| , resolution 2.35Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | |||||||
| Activity: | Protein-tyrosine-phosphatase, with EC number 3.1.3.48 | ||||||
| Related: | 1ECV, 1C83, 1C85, 1C86, 1C87, 1C88
| ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
CRYSTAL STRUCTURE OF PROTEIN TYROSINE PHOSPHATASE 1B COMPLEXED WITH 3-(OXALYL-AMINO)-NAPHTHALENE-2-CARBOXLIC ACID
OverviewOverview
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.
About this StructureAbout this Structure
1C84 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
ReferenceReference
2-(oxalylamino)-benzoic acid is a general, competitive inhibitor of protein-tyrosine phosphatases., Andersen HS, Iversen LF, Jeppesen CB, Branner S, Norris K, Rasmussen HB, Moller KB, Moller NP, J Biol Chem. 2000 Mar 10;275(10):7101-8. PMID:10702277
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