1c85: Difference between revisions
New page: left|200px<br /> <applet load="1c85" size="450" color="white" frame="true" align="right" spinBox="true" caption="1c85, resolution 2.72Å" /> '''CRYSTAL STRUCTURE O... |
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[[Image:1c85.gif|left|200px]]<br /> | [[Image:1c85.gif|left|200px]]<br /><applet load="1c85" size="350" color="white" frame="true" align="right" spinBox="true" | ||
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caption="1c85, resolution 2.72Å" /> | caption="1c85, resolution 2.72Å" /> | ||
'''CRYSTAL STRUCTURE OF PROTEIN TYROSINE PHOSPHATASE 1B COMPLEXED WITH 2-(OXALYL-AMINO)-BENZOIC ACID'''<br /> | '''CRYSTAL STRUCTURE OF PROTEIN TYROSINE PHOSPHATASE 1B COMPLEXED WITH 2-(OXALYL-AMINO)-BENZOIC ACID'''<br /> | ||
==Overview== | ==Overview== | ||
Protein-tyrosine phosphatases (PTPs) are critically involved in regulation | 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. | ||
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
1C85 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with OBA as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [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] Full crystallographic information is available from [http:// | 1C85 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=OBA:'>OBA</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [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] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1C85 OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: Protein-tyrosine-phosphatase]] | [[Category: Protein-tyrosine-phosphatase]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Andersen, H | [[Category: Andersen, H S.]] | ||
[[Category: Branner, S.]] | [[Category: Branner, S.]] | ||
[[Category: Iversen, L | [[Category: Iversen, L F.]] | ||
[[Category: Moller, N | [[Category: Moller, N P.]] | ||
[[Category: Rasmussen, H | [[Category: Rasmussen, H B.]] | ||
[[Category: OBA]] | [[Category: OBA]] | ||
[[Category: hydrolase]] | [[Category: hydrolase]] | ||
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[[Category: phosphorylation]] | [[Category: phosphorylation]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:03:23 2008'' | ||
Revision as of 13:03, 21 February 2008
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CRYSTAL STRUCTURE OF PROTEIN TYROSINE PHOSPHATASE 1B COMPLEXED WITH 2-(OXALYL-AMINO)-BENZOIC 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.
DiseaseDisease
Known diseases associated with this structure: Abdominal body fat distribution, modifier of OMIM:[176885], Insulin resistance, susceptibility to OMIM:[176885]
About this StructureAbout this Structure
1C85 is a Single protein structure of sequence from Homo sapiens with as ligand. Active as Protein-tyrosine-phosphatase, with EC number 3.1.3.48 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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