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[[Image:1t4j.jpg|left|200px]]<br /><applet load="1t4j" size="350" color="white" frame="true" align="right" spinBox="true"
caption="1t4j, resolution 2.70&Aring;" />
'''Allosteric Inhibition of Protein Tyrosine Phosphatase 1B'''<br />


==Overview==
==Allosteric Inhibition of Protein Tyrosine Phosphatase 1B==
Obesity and type II diabetes are closely linked metabolic syndromes that, afflict &gt;100 million people worldwide. Although protein tyrosine, phosphatase 1B (PTP1B) has emerged as a promising target for the treatment, of both syndromes, the discovery of pharmaceutically acceptable inhibitors, that bind at the active site remains a substantial challenge. Here we, describe the discovery of an allosteric site in PTP1B. Crystal structures, of PTP1B in complex with allosteric inhibitors reveal a novel site located, approximately 20 A from the catalytic site. We show that allosteric, inhibitors prevent formation of the active form of the enzyme by blocking, mobility of the catalytic loop, thereby exploiting a general mechanism, used by tyrosine phosphatases. Notably, these inhibitors exhibit, selectivity for PTP1B and enhance insulin signaling in cells. Allosteric, inhibition is a promising strategy for targeting PTP1B and constitutes a, mechanism that may be applicable to other tyrosine phosphatases.
<StructureSection load='1t4j' size='340' side='right'caption='[[1t4j]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[1t4j]] 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=1T4J OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1T4J 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]] 2.7&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FRJ:3-(3,5-DIBROMO-4-HYDROXY-BENZOYL)-2-ETHYL-BENZOFURAN-6-SULFONIC+ACID+[4-(THIAZOL-2-YLSULFAMOYL)-PHENYL]-AMIDE'>FRJ</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=1t4j FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1t4j OCA], [https://pdbe.org/1t4j PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1t4j RCSB], [https://www.ebi.ac.uk/pdbsum/1t4j PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1t4j 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/t4/1t4j_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=1t4j ConSurf].
<div style="clear:both"></div>


==Disease==
==See Also==
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]]
*[[Tyrosine phosphatase 3D structures|Tyrosine phosphatase 3D structures]]
 
== References ==
==About this Structure==
<references/>
1T4J is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=FRJ:'>FRJ</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [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] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1T4J OCA].
__TOC__
 
</StructureSection>
==Reference==
Allosteric inhibition of protein tyrosine phosphatase 1B., Wiesmann C, Barr KJ, Kung J, Zhu J, Erlanson DA, Shen W, Fahr BJ, Zhong M, Taylor L, Randal M, McDowell RS, Hansen SK, Nat Struct Mol Biol. 2004 Aug;11(8):730-7. Epub 2004 Jul 18. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=15258570 15258570]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Protein-tyrosine-phosphatase]]
[[Category: Large Structures]]
[[Category: Single protein]]
[[Category: Barr KJ]]
[[Category: Barr, K.J.]]
[[Category: Fahr BJ]]
[[Category: Fahr, B.J.]]
[[Category: Hansen SK]]
[[Category: Hansen, S.K.]]
[[Category: Kung J]]
[[Category: Kung, J.]]
[[Category: McDowell RS]]
[[Category: McDowell, R.S.]]
[[Category: Randal M]]
[[Category: Randal, M.]]
[[Category: Shen W]]
[[Category: Shen, W.]]
[[Category: Taylor L]]
[[Category: Taylor, L.]]
[[Category: Wiesmann C]]
[[Category: Wiesmann, C.]]
[[Category: Zhong M]]
[[Category: Zhong, M.]]
[[Category: Zhu J]]
[[Category: Zhu, J.]]
[[Category: FRJ]]
[[Category: allosteric inhibition protein tyrosine phosphatase 1b]]
 
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri Feb 15 16:55:15 2008''

Latest revision as of 11:35, 14 February 2024

Allosteric Inhibition of Protein Tyrosine Phosphatase 1BAllosteric Inhibition of Protein Tyrosine Phosphatase 1B

Structural highlights

1t4j is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.7Å
Ligands:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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.

See Also

References

  1. ↑ 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
  2. ↑ 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

1t4j, resolution 2.70Å

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