1pxh
From Proteopedia
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|PDB= 1pxh |SIZE=350|CAPTION= <scene name='initialview01'>1pxh</scene>, resolution 2.15Å | |PDB= 1pxh |SIZE=350|CAPTION= <scene name='initialview01'>1pxh</scene>, resolution 2.15Å | ||
|SITE= | |SITE= | ||
| - | |LIGAND= <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SNA:N-{1-[5-(1-CARBAMOYL-2-MERCAPTO-ETHYLCARBAMOYL)-PENTYLCARBAMOYL]-2-[4-(DIFLUORO-PHOSPHONO-METHYL)-PHENYL]-ETHYL}-3-{2-[4-(DIFLUORO-PHOSPHONO-METHYL)-PHENYL]-ACETYLAMINO}-SUCCINAMIC+ACID'>SNA</scene> | + | |LIGAND= <scene name='pdbligand=ACY:ACETIC+ACID'>ACY</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SNA:N-{1-[5-(1-CARBAMOYL-2-MERCAPTO-ETHYLCARBAMOYL)-PENTYLCARBAMOYL]-2-[4-(DIFLUORO-PHOSPHONO-METHYL)-PHENYL]-ETHYL}-3-{2-[4-(DIFLUORO-PHOSPHONO-METHYL)-PHENYL]-ACETYLAMINO}-SUCCINAMIC+ACID'>SNA</scene> |
| - | + | |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= ptp1b ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | |GENE= ptp1b ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY=[[1n6w|1N6W]] | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1pxh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1pxh OCA], [http://www.ebi.ac.uk/pdbsum/1pxh PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1pxh RCSB]</span> | ||
}} | }} | ||
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==Overview== | ==Overview== | ||
Protein-tyrosine phosphatase 1B (PTP1B) has been implicated as an important regulator in several signaling pathways including those initiated by insulin and leptin. Potent and specific PTP1B inhibitors could serve as useful tools in elucidating the physiological functions of PTP1B and may constitute valuable therapeutics in the treatment of several human diseases. We have determined the crystal structure of PTP1B in complex with compound 2, the most potent and selective PTP1B inhibitor reported to date. The structure at 2.15-A resolution reveals that compound 2 simultaneously binds to the active site and a unique proximal noncatalytic site formed by Lys-41, Arg-47, and Asp-48. The structural data are further corroborated by results from kinetic analyses of the interactions of PTP1B and its site-directed mutants with compound 2 and several of its variants. Although many of the residues important for interactions between PTP1B and compound 2 are not unique to PTP1B, the combinations of all contact residues differ between PTP isozymes, which provide a structural basis for potent and selective PTP1B inhibition. Our data further suggest that potent, yet highly selective, PTP1B inhibitory agents can be acquired by targeting the area defined by residues Lys-41, Arg-47, and Asp-48, in addition to the previously identified second aryl phosphate-binding pocket. | Protein-tyrosine phosphatase 1B (PTP1B) has been implicated as an important regulator in several signaling pathways including those initiated by insulin and leptin. Potent and specific PTP1B inhibitors could serve as useful tools in elucidating the physiological functions of PTP1B and may constitute valuable therapeutics in the treatment of several human diseases. We have determined the crystal structure of PTP1B in complex with compound 2, the most potent and selective PTP1B inhibitor reported to date. The structure at 2.15-A resolution reveals that compound 2 simultaneously binds to the active site and a unique proximal noncatalytic site formed by Lys-41, Arg-47, and Asp-48. The structural data are further corroborated by results from kinetic analyses of the interactions of PTP1B and its site-directed mutants with compound 2 and several of its variants. Although many of the residues important for interactions between PTP1B and compound 2 are not unique to PTP1B, the combinations of all contact residues differ between PTP isozymes, which provide a structural basis for potent and selective PTP1B inhibition. Our data further suggest that potent, yet highly selective, PTP1B inhibitory agents can be acquired by targeting the area defined by residues Lys-41, Arg-47, and Asp-48, in addition to the previously identified second aryl phosphate-binding pocket. | ||
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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: Sun, J P.]] | [[Category: Sun, J P.]] | ||
[[Category: Zhang, Z Y.]] | [[Category: Zhang, Z Y.]] | ||
| - | [[Category: ACY]] | ||
| - | [[Category: MG]] | ||
| - | [[Category: SNA]] | ||
[[Category: phosphatase inhibitor]] | [[Category: phosphatase inhibitor]] | ||
[[Category: protein tyrosine phosphatase]] | [[Category: protein tyrosine phosphatase]] | ||
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[[Category: x-ray diffraction]] | [[Category: x-ray diffraction]] | ||
| - | ''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 23:05:57 2008'' |
Revision as of 20:06, 30 March 2008
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| , resolution 2.15Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | , , | ||||||
| Gene: | ptp1b (Homo sapiens) | ||||||
| Activity: | Protein-tyrosine-phosphatase, with EC number 3.1.3.48 | ||||||
| Related: | 1N6W
| ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Crystal structure of protein tyrosine phosphatase 1B with potent and selective bidentate inhibitor compound 2
Overview
Protein-tyrosine phosphatase 1B (PTP1B) has been implicated as an important regulator in several signaling pathways including those initiated by insulin and leptin. Potent and specific PTP1B inhibitors could serve as useful tools in elucidating the physiological functions of PTP1B and may constitute valuable therapeutics in the treatment of several human diseases. We have determined the crystal structure of PTP1B in complex with compound 2, the most potent and selective PTP1B inhibitor reported to date. The structure at 2.15-A resolution reveals that compound 2 simultaneously binds to the active site and a unique proximal noncatalytic site formed by Lys-41, Arg-47, and Asp-48. The structural data are further corroborated by results from kinetic analyses of the interactions of PTP1B and its site-directed mutants with compound 2 and several of its variants. Although many of the residues important for interactions between PTP1B and compound 2 are not unique to PTP1B, the combinations of all contact residues differ between PTP isozymes, which provide a structural basis for potent and selective PTP1B inhibition. Our data further suggest that potent, yet highly selective, PTP1B inhibitory agents can be acquired by targeting the area defined by residues Lys-41, Arg-47, and Asp-48, in addition to the previously identified second aryl phosphate-binding pocket.
About this Structure
1PXH is a Single protein structure of sequence from Homo sapiens. This structure supersedes the now removed PDB entry 1N6W. Full crystallographic information is available from OCA.
Reference
Crystal structure of PTP1B complexed with a potent and selective bidentate inhibitor., Sun JP, Fedorov AA, Lee SY, Guo XL, Shen K, Lawrence DS, Almo SC, Zhang ZY, J Biol Chem. 2003 Apr 4;278(14):12406-14. Epub 2003 Jan 23. PMID:12547827
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