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== | ==Structural Basis for Inhibition of Protein Tyrosine Phosphatase 1B by Isothiazolidinone Heterocyclic Phosphonate Mimetics== | ||
Crystal structures of protein-tyrosine phosphatase 1B in complex with | <StructureSection load='2cm7' size='340' side='right'caption='[[2cm7]], [[Resolution|resolution]] 2.10Å' scene=''> | ||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[2cm7]] 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=2CM7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2CM7 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]] 2.1Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=IZD:ISOTHIAZOLIDINONE+ANALOG'>IZD</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=2cm7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2cm7 OCA], [https://pdbe.org/2cm7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2cm7 RCSB], [https://www.ebi.ac.uk/pdbsum/2cm7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2cm7 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> | |||
== Evolutionary Conservation == | |||
[[Image:Consurf_key_small.gif|200px|right]] | |||
Check<jmol> | |||
<jmolCheckbox> | |||
<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/cm/2cm7_consurf.spt"</scriptWhenChecked> | |||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | |||
<text>to colour the structure by Evolutionary Conservation</text> | |||
</jmolCheckbox> | |||
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2cm7 ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Crystal structures of protein-tyrosine phosphatase 1B in complex with compounds bearing a novel isothiazolidinone (IZD) heterocyclic phosphonate mimetic reveal that the heterocycle is highly complementary to the catalytic pocket of the protein. The heterocycle participates in an extensive network of hydrogen bonds with the backbone of the phosphate-binding loop, Phe(182) of the flap, and the side chain of Arg(221). When substituted with a phenol, the small inhibitor induces the closed conformation of the protein and displaces all waters in the catalytic pocket. Saturated IZD-containing peptides are more potent inhibitors than unsaturated analogs because the IZD heterocycle and phenyl ring directly attached to it bind in a nearly orthogonal orientation with respect to each other, a conformation that is close to the energy minimum of the saturated IZD-phenyl moiety. These results explain why the heterocycle is a potent phosphonate mimetic and an ideal starting point for designing small nonpeptidic inhibitors. | |||
Structural basis for inhibition of protein-tyrosine phosphatase 1B by isothiazolidinone heterocyclic phosphonate mimetics.,Ala PJ, Gonneville L, Hillman MC, Becker-Pasha M, Wei M, Reid BG, Klabe R, Yue EW, Wayland B, Douty B, Polam P, Wasserman Z, Bower M, Combs AP, Burn TC, Hollis GF, Wynn R J Biol Chem. 2006 Oct 27;281(43):32784-95. Epub 2006 Aug 17. PMID:16916797<ref>PMID:16916797</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 2cm7" style="background-color:#fffaf0;"></div> | |||
== | ==See Also== | ||
*[[Tyrosine phosphatase 3D structures|Tyrosine phosphatase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: Ala PJ]] | |||
[[Category: Ala | [[Category: Becker-Pasha M]] | ||
[[Category: Becker-Pasha | [[Category: Bower M]] | ||
[[Category: Bower | [[Category: Burn TC]] | ||
[[Category: Burn | [[Category: Combs AP]] | ||
[[Category: Combs | [[Category: Douty B]] | ||
[[Category: Douty | [[Category: Gonneville L]] | ||
[[Category: Gonneville | [[Category: Hillman MC]] | ||
[[Category: Hillman | [[Category: Hollis GF]] | ||
[[Category: Hollis | [[Category: Klabe R]] | ||
[[Category: Klabe | [[Category: Polam P]] | ||
[[Category: Polam | [[Category: Reid BG]] | ||
[[Category: Reid | [[Category: Wasserman Z]] | ||
[[Category: Wasserman | [[Category: Wayland B]] | ||
[[Category: Wayland | [[Category: Wei M]] | ||
[[Category: Wei | [[Category: Wynn R]] | ||
[[Category: Wynn | [[Category: Yue EW]] | ||
[[Category: Yue | |||
Latest revision as of 17:21, 13 December 2023
Structural Basis for Inhibition of Protein Tyrosine Phosphatase 1B by Isothiazolidinone Heterocyclic Phosphonate MimeticsStructural Basis for Inhibition of Protein Tyrosine Phosphatase 1B by Isothiazolidinone Heterocyclic Phosphonate Mimetics
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] 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 PubMedCrystal structures of protein-tyrosine phosphatase 1B in complex with compounds bearing a novel isothiazolidinone (IZD) heterocyclic phosphonate mimetic reveal that the heterocycle is highly complementary to the catalytic pocket of the protein. The heterocycle participates in an extensive network of hydrogen bonds with the backbone of the phosphate-binding loop, Phe(182) of the flap, and the side chain of Arg(221). When substituted with a phenol, the small inhibitor induces the closed conformation of the protein and displaces all waters in the catalytic pocket. Saturated IZD-containing peptides are more potent inhibitors than unsaturated analogs because the IZD heterocycle and phenyl ring directly attached to it bind in a nearly orthogonal orientation with respect to each other, a conformation that is close to the energy minimum of the saturated IZD-phenyl moiety. These results explain why the heterocycle is a potent phosphonate mimetic and an ideal starting point for designing small nonpeptidic inhibitors. Structural basis for inhibition of protein-tyrosine phosphatase 1B by isothiazolidinone heterocyclic phosphonate mimetics.,Ala PJ, Gonneville L, Hillman MC, Becker-Pasha M, Wei M, Reid BG, Klabe R, Yue EW, Wayland B, Douty B, Polam P, Wasserman Z, Bower M, Combs AP, Burn TC, Hollis GF, Wynn R J Biol Chem. 2006 Oct 27;281(43):32784-95. Epub 2006 Aug 17. PMID:16916797[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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