1c86: Difference between revisions
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|PDB= 1c86 |SIZE=350|CAPTION= <scene name='initialview01'>1c86</scene>, resolution 2.3Å | |PDB= 1c86 |SIZE=350|CAPTION= <scene name='initialview01'>1c86</scene>, resolution 2.3Å | ||
|SITE= | |SITE= | ||
|LIGAND= <scene name='pdbligand=OPA:2-(OXALYL-AMINO)-4,7-DIHYDRO-5H-THIENO[2,3-C]PYRAN-3-CARBOXYLIC ACID'>OPA</scene> | |LIGAND= <scene name='pdbligand=OPA:2-(OXALYL-AMINO)-4,7-DIHYDRO-5H-THIENO[2,3-C]PYRAN-3-CARBOXYLIC+ACID'>OPA</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]], [[1c87|1C87]], [[1c88|1C88]] | |||
|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1c86 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1c86 OCA], [http://www.ebi.ac.uk/pdbsum/1c86 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1c86 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. | ||
==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: 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 19:16:30 2008'' | ||
