1c88
From Proteopedia
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|PDB= 1c88 |SIZE=350|CAPTION= <scene name='initialview01'>1c88</scene>, resolution 1.8Å | |PDB= 1c88 |SIZE=350|CAPTION= <scene name='initialview01'>1c88</scene>, resolution 1.8Å | ||
|SITE= | |SITE= | ||
| - | |LIGAND= <scene name='pdbligand=OTA:2-(OXALYL-AMINO)-4,5,6,7-TETRAHYDRO-THIENO[2,3-C]PYRIDINE-3-CARBOXYLIC ACID'>OTA</scene> | + | |LIGAND= <scene name='pdbligand=OTA:2-(OXALYL-AMINO)-4,5,6,7-TETRAHYDRO-THIENO[2,3-C]PYRIDINE-3-CARBOXYLIC+ACID'>OTA</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]], [[1c84|1C84]], [[1c85|1C85]], [[1c86|1C86]], [[1c87|1C87]] | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1c88 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1c88 OCA], [http://www.ebi.ac.uk/pdbsum/1c88 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1c88 RCSB]</span> | ||
}} | }} | ||
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==Overview== | ==Overview== | ||
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. | 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. | ||
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| - | ==Disease== | ||
| - | Known diseases associated with this structure: Abdominal body fat distribution, modifier of OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176885 176885]], Insulin resistance, susceptibility to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176885 176885]] | ||
==About this Structure== | ==About this Structure== | ||
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[[Category: Moller, N P.]] | [[Category: Moller, N P.]] | ||
[[Category: Mortensen, S B.]] | [[Category: Mortensen, S B.]] | ||
| - | [[Category: OTA]] | ||
[[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 19:16:39 2008'' |
Revision as of 16:16, 30 March 2008
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| , resolution 1.8Å | |||||||
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| Ligands: | |||||||
| Activity: | Protein-tyrosine-phosphatase, with EC number 3.1.3.48 | ||||||
| Related: | 1ECV, 1C83, 1C84, 1C85, 1C86, 1C87
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| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
CRYSTAL STRUCTURE OF PROTEIN TYROSINE PHOSPHATASE 1B COMPLEXED WITH 2-(OXALYL-AMINO)-4,5,6,7-TETRAHYDRO-THIENO[2,3-C]PYRIDINE-3-CARBOXYLIC ACID
Overview
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.
About this Structure
1C88 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Structure-based design of a low molecular weight, nonphosphorus, nonpeptide, and highly selective inhibitor of protein-tyrosine phosphatase 1B., Iversen LF, Andersen HS, Branner S, Mortensen SB, Peters GH, Norris K, Olsen OH, Jeppesen CB, Lundt BF, Ripka W, Moller KB, Moller NP, J Biol Chem. 2000 Apr 7;275(14):10300-7. PMID:10744717
Page seeded by OCA on Sun Mar 30 19:16:39 2008
