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| | ==Multiconformer model of apo K197C PTP1B at 100 K== | | ==Multiconformer model of apo K197C PTP1B at 100 K== |
| - | <StructureSection load='6bai' size='340' side='right' caption='[[6bai]], [[Resolution|resolution]] 1.95Å' scene=''> | + | <StructureSection load='6bai' size='340' side='right'caption='[[6bai]], [[Resolution|resolution]] 1.95Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6bai]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6BAI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6BAI FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6bai]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6BAI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6BAI FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=TRS:2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>TRS</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]] 1.95Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6b90|6b90]], [[6b8e|6b8e]], [[6b8t|6b8t]], [[6b8x|6b8x]], [[6b8z|6b8z]], [[6b95|6b95]]</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=TRS:2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>TRS</scene></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'>[https://proteopedia.org/fgij/fg.htm?mol=6bai FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6bai OCA], [https://pdbe.org/6bai PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6bai RCSB], [https://www.ebi.ac.uk/pdbsum/6bai PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6bai ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6bai FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6bai OCA], [http://pdbe.org/6bai PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6bai RCSB], [http://www.ebi.ac.uk/pdbsum/6bai PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6bai 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> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Protein-tyrosine-phosphatase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Biel, J T]] | + | [[Category: Large Structures]] |
| - | [[Category: Brandao-Neto, J]] | + | [[Category: Biel JT]] |
| - | [[Category: Delft, F von]] | + | [[Category: Brandao-Neto J]] |
| - | [[Category: Fraser, J S]] | + | [[Category: Fraser JS]] |
| - | [[Category: Hill, Z B]] | + | [[Category: Hill ZB]] |
| - | [[Category: Kang, E]] | + | [[Category: Kang E]] |
| - | [[Category: Keedy, D A]] | + | [[Category: Keedy DA]] |
| - | [[Category: Rettenmaier, T J]] | + | [[Category: Rettenmaier TJ]] |
| - | [[Category: Wells, J A]] | + | [[Category: Wells JA]] |
| - | [[Category: Allostery]] | + | [[Category: Von Delft F]] |
| - | [[Category: Enzyme]]
| + | |
| - | [[Category: Multiconformer]]
| + | |
| - | [[Category: Multitemperature]]
| + | |
| - | [[Category: Protein tyrosine phosphatase]]
| + | |
| - | [[Category: Protein tyrosine phosphatase 1b]]
| + | |
| - | [[Category: Ptp]]
| + | |
| - | [[Category: Ptp1b]]
| + | |
| - | [[Category: Signaling protein]]
| + | |
| 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]
Publication Abstract from PubMed
Allostery is an inherent feature of proteins, but it remains challenging to reveal the mechanisms by which allosteric signals propagate. A clearer understanding of this intrinsic circuitry would afford new opportunities to modulate protein function. Here we have identified allosteric sites in protein tyrosine phosphatase 1B (PTP1B) by combining multiple-temperature X-ray crystallography experiments and structure determination from hundreds of individual small-molecule fragment soaks. New modeling approaches reveal 'hidden' low-occupancy conformational states for protein and ligands. Our results converge on allosteric sites that are conformationally coupled to the active-site WPD loop and are hotspots for fragment binding. Targeting one of these sites with covalently tethered molecules or mutations allosterically inhibits enzyme activity. Overall, this work demonstrates how the ensemble nature of macromolecular structure, revealed here by multitemperature crystallography, can elucidate allosteric mechanisms and open new doors for long-range control of protein function.
An expanded allosteric network in PTP1B by multitemperature crystallography, fragment screening, and covalent tethering.,Keedy DA, Hill ZB, Biel JT, Kang E, Rettenmaier TJ, Brandao-Neto J, Pearce NM, von Delft F, Wells JA, Fraser JS Elife. 2018 Jun 7;7. pii: 36307. doi: 10.7554/eLife.36307. PMID:29877794[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
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
- ↑ Keedy DA, Hill ZB, Biel JT, Kang E, Rettenmaier TJ, Brandao-Neto J, Pearce NM, von Delft F, Wells JA, Fraser JS. An expanded allosteric network in PTP1B by multitemperature crystallography, fragment screening, and covalent tethering. Elife. 2018 Jun 7;7. pii: 36307. doi: 10.7554/eLife.36307. PMID:29877794 doi:http://dx.doi.org/10.7554/eLife.36307
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