1t49

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[[Image:1t49.jpg|left|200px]]<br /><applet load="1t49" size="350" color="white" frame="true" align="right" spinBox="true"
 
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caption="1t49, resolution 1.90&Aring;" />
 
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'''Allosteric Inhibition of Protein Tyrosine Phosphatase 1B'''<br />
 
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==Overview==
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==Allosteric Inhibition of Protein Tyrosine Phosphatase 1B==
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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.
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<StructureSection load='1t49' size='340' side='right'caption='[[1t49]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1t49]] 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=1T49 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1T49 FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.9&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=892:3-(3,5-DIBROMO-4-HYDROXY-BENZOYL)-2-ETHYL-BENZOFURAN-6-SULFONIC+ACID+(4-SULFAMOYL-PHENYL)-AMIDE'>892</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1t49 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1t49 OCA], [https://pdbe.org/1t49 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1t49 RCSB], [https://www.ebi.ac.uk/pdbsum/1t49 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1t49 ProSAT]</span></td></tr>
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</table>
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== Function ==
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[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>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/t4/1t49_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</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=1t49 ConSurf].
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<div style="clear:both"></div>
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==Disease==
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==See Also==
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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]]
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*[[Tyrosine phosphatase 3D structures|Tyrosine phosphatase 3D structures]]
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== References ==
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==About this Structure==
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<references/>
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1T49 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=MG:'>MG</scene> and <scene name='pdbligand=892:'>892</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. 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=1T49 OCA].
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__TOC__
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</StructureSection>
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==Reference==
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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]
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[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Protein-tyrosine-phosphatase]]
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[[Category: Large Structures]]
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[[Category: Single protein]]
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[[Category: Barr KJ]]
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[[Category: Barr, K J.]]
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[[Category: Fahr BJ]]
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[[Category: Fahr, B J.]]
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[[Category: Hansen SK]]
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[[Category: Hansen, S K.]]
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[[Category: Kung J]]
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[[Category: Kung, J.]]
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[[Category: McDowell RS]]
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[[Category: McDowell, R S.]]
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[[Category: Randal M]]
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[[Category: Randal, M.]]
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[[Category: Shen W]]
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[[Category: Shen, W.]]
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[[Category: Taylor L]]
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[[Category: Taylor, L.]]
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[[Category: Wiesmann C]]
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[[Category: Wiesmann, C.]]
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[[Category: Zhong M]]
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[[Category: Zhong, M.]]
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[[Category: Zhu J]]
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[[Category: Zhu, J.]]
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[[Category: 892]]
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[[Category: MG]]
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[[Category: allosteric inhibition]]
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[[Category: protein tyrosine phosphatase 1b]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:09:41 2008''
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Current revision

Allosteric Inhibition of Protein Tyrosine Phosphatase 1B

PDB ID 1t49

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