6b95: Difference between revisions
New page: '''Unreleased structure''' The entry 6b95 is ON HOLD until Paper Publication Authors: Keedy, D.A., Hill, Z.B., Biel, J.T., Kang, E., Rettenmaier, T.J., Brandao-Neto, J., von Delft, F., ... |
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==Multiconformer model of K197C PTP1B tethered to compound 2 at 100 K== | |||
<StructureSection load='6b95' size='340' side='right'caption='[[6b95]], [[Resolution|resolution]] 1.95Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6b95]] 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=6B95 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6B95 FirstGlance]. <br> | |||
</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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=D0P:~{N}-[5-[2,4-bis(fluoranyl)phenyl]-2-oxidanyl-phenyl]-2-sulfanyl-ethanamide'>D0P</scene>, <scene name='pdbligand=TRS:2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>TRS</scene></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=6b95 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6b95 OCA], [https://pdbe.org/6b95 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6b95 RCSB], [https://www.ebi.ac.uk/pdbsum/6b95 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6b95 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[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;"> | |||
== 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<ref>PMID:29877794</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 6b95" style="background-color:#fffaf0;"></div> | ||
[[Category: | == References == | ||
[[Category: Brandao-Neto | <references/> | ||
[[Category: | __TOC__ | ||
[[Category: | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Biel JT]] | ||
[[Category: Von Delft | [[Category: Brandao-Neto J]] | ||
[[Category: Fraser JS]] | |||
[[Category: Hill ZB]] | |||
[[Category: Kang E]] | |||
[[Category: Keedy DA]] | |||
[[Category: Rettenmaier TJ]] | |||
[[Category: Wells JA]] | |||
[[Category: Von Delft F]] | |||
Latest revision as of 14:02, 30 October 2024
Multiconformer model of K197C PTP1B tethered to compound 2 at 100 KMulticonformer model of K197C PTP1B tethered to compound 2 at 100 K
Structural highlights
FunctionPTN1_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 PubMedAllostery 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
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