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| | <StructureSection load='1pxh' size='340' side='right'caption='[[1pxh]], [[Resolution|resolution]] 2.15Å' scene=''> | | <StructureSection load='1pxh' size='340' side='right'caption='[[1pxh]], [[Resolution|resolution]] 2.15Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[1pxh]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=1n6w 1n6w]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1PXH OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=1PXH FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[1pxh]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=1n6w 1n6w]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1PXH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1PXH FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.15Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1n6w|1n6w]]</div></td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ptp1b ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1pxh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1pxh OCA], [https://pdbe.org/1pxh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1pxh RCSB], [https://www.ebi.ac.uk/pdbsum/1pxh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1pxh ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><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></td></tr>
| + | |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=1pxh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1pxh OCA], [http://pdbe.org/1pxh PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1pxh RCSB], [http://www.ebi.ac.uk/pdbsum/1pxh PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1pxh ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/PTN1_HUMAN PTN1_HUMAN]] Tyrosine-protein phosphatase which acts as a regulator of endoplasmic reticulum unfolded protein response. Mediates dephosphorylation of EIF2AK3/PERK; inactivating the protein kinase activity of EIF2AK3/PERK. May play an important role in CKII- and p60c-src-induced signal transduction cascades. May regulate the EFNA5-EPHA3 signaling pathway which modulates cell reorganization and cell-cell repulsion.<ref>PMID:21135139</ref> <ref>PMID:22169477</ref> | + | [https://www.uniprot.org/uniprot/PTN1_HUMAN PTN1_HUMAN] Tyrosine-protein phosphatase which acts as a regulator of endoplasmic reticulum unfolded protein response. Mediates dephosphorylation of EIF2AK3/PERK; inactivating the protein kinase activity of EIF2AK3/PERK. May play an important role in CKII- and p60c-src-induced signal transduction cascades. May regulate the EFNA5-EPHA3 signaling pathway which modulates cell reorganization and cell-cell repulsion.<ref>PMID:21135139</ref> <ref>PMID:22169477</ref> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Protein-tyrosine-phosphatase]]
| + | [[Category: Almo SC]] |
| - | [[Category: Almo, S C]] | + | [[Category: Fedorov A]] |
| - | [[Category: Fedorov, A]] | + | [[Category: Guo XL]] |
| - | [[Category: Guo, X L]] | + | [[Category: Lawrence DS]] |
| - | [[Category: Lawrence, D S]] | + | [[Category: Lee SY]] |
| - | [[Category: Lee, S Y]] | + | [[Category: Shen K]] |
| - | [[Category: Shen, K]] | + | [[Category: Sun JP]] |
| - | [[Category: Sun, J P]] | + | [[Category: Zhang ZY]] |
| - | [[Category: Zhang, Z Y]] | + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Phosphatase inhibitor]]
| + | |
| - | [[Category: Protein tyrosine phosphatase]]
| + | |
| - | [[Category: Ptp1b]]
| + | |
| Structural highlights
Function
PTN1_HUMAN Tyrosine-protein phosphatase which acts as a regulator of endoplasmic reticulum unfolded protein response. Mediates dephosphorylation of EIF2AK3/PERK; inactivating the protein kinase activity of EIF2AK3/PERK. May play an important role in CKII- and p60c-src-induced signal transduction cascades. May regulate the EFNA5-EPHA3 signaling pathway which modulates cell reorganization and cell-cell repulsion.[1] [2]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
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.
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[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Nievergall E, Janes PW, Stegmayer C, Vail ME, Haj FG, Teng SW, Neel BG, Bastiaens PI, Lackmann M. PTP1B regulates Eph receptor function and trafficking. J Cell Biol. 2010 Dec 13;191(6):1189-203. doi: 10.1083/jcb.201005035. Epub 2010, Dec 6. PMID:21135139 doi:10.1083/jcb.201005035
- ↑ Krishnan N, Fu C, Pappin DJ, Tonks NK. H2S-Induced sulfhydration of the phosphatase PTP1B and its role in the endoplasmic reticulum stress response. Sci Signal. 2011 Dec 13;4(203):ra86. doi: 10.1126/scisignal.2002329. PMID:22169477 doi:10.1126/scisignal.2002329
- ↑ Sun JP, Fedorov AA, Lee SY, Guo XL, Shen K, Lawrence DS, Almo SC, Zhang ZY. Crystal structure of PTP1B complexed with a potent and selective bidentate inhibitor. J Biol Chem. 2003 Apr 4;278(14):12406-14. Epub 2003 Jan 23. PMID:12547827 doi:10.1074/jbc.M212491200
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