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New page: left|200px<br /> <applet load="1q1m" size="450" color="white" frame="true" align="right" spinBox="true" caption="1q1m, resolution 2.60Å" /> '''A Highly Efficient ...
 
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[[Image:1q1m.gif|left|200px]]<br />
<applet load="1q1m" size="450" color="white" frame="true" align="right" spinBox="true"
caption="1q1m, resolution 2.60&Aring;" />
'''A Highly Efficient Approach to a Selective and Cell Active PTP1B inhibitors'''<br />


==Overview==
==A Highly Efficient Approach to a Selective and Cell Active PTP1B inhibitors==
Using an NMR-based fragment screening and X-ray crystal structure-based, assembly, starting with millimolar ligands for both the catalytic site and, the second phosphotyrosine binding site, we have identified a, small-molecule inhibitor of protein tyrosine phosphatase 1B with low, micromolar inhibition constant, high selectivity (30-fold) over the highly, homologous T-cell protein tyrosine phosphatase, and good cellular activity, in COS-7 cells.
<StructureSection load='1q1m' size='340' side='right'caption='[[1q1m]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[1q1m]] 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=1Q1M OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1Q1M 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]] 2.6&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=234:5-{2-FLUORO-5-[3-(3-HYDROXY-2-METHOXYCARBONYL-PHENOXY)-PROPENYL]-PHENYL}-ISOXAZOLE-3-CARBOXYLIC+ACID'>234</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=1q1m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1q1m OCA], [https://pdbe.org/1q1m PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1q1m RCSB], [https://www.ebi.ac.uk/pdbsum/1q1m PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1q1m 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/q1/1q1m_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=1q1m ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Using an NMR-based fragment screening and X-ray crystal structure-based assembly, starting with millimolar ligands for both the catalytic site and the second phosphotyrosine binding site, we have identified a small-molecule inhibitor of protein tyrosine phosphatase 1B with low micromolar inhibition constant, high selectivity (30-fold) over the highly homologous T-cell protein tyrosine phosphatase, and good cellular activity in COS-7 cells.


==Disease==
Fragment screening and assembly: a highly efficient approach to a selective and cell active protein tyrosine phosphatase 1B inhibitor.,Liu G, Xin Z, Pei Z, Hajduk PJ, Abad-Zapatero C, Hutchins CW, Zhao H, Lubben TH, Ballaron SJ, Haasch DL, Kaszubska W, Rondinone CM, Trevillyan JM, Jirousek MR J Med Chem. 2003 Sep 25;46(20):4232-5. PMID:13678400<ref>PMID:13678400</ref>
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]]


==About this Structure==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
1Q1M 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 234 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://ispc.weizmann.ac.il/oca-bin/ocashort?id=1Q1M OCA].
</div>
<div class="pdbe-citations 1q1m" style="background-color:#fffaf0;"></div>


==Reference==
==See Also==
Fragment screening and assembly: a highly efficient approach to a selective and cell active protein tyrosine phosphatase 1B inhibitor., Liu G, Xin Z, Pei Z, Hajduk PJ, Abad-Zapatero C, Hutchins CW, Zhao H, Lubben TH, Ballaron SJ, Haasch DL, Kaszubska W, Rondinone CM, Trevillyan JM, Jirousek MR, J Med Chem. 2003 Sep 25;46(20):4232-5. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=13678400 13678400]
*[[Tyrosine phosphatase 3D structures|Tyrosine phosphatase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Protein-tyrosine-phosphatase]]
[[Category: Large Structures]]
[[Category: Single protein]]
[[Category: Abad-Zapatero C]]
[[Category: Abad-Zapatero, C.]]
[[Category: Ballaron SJ]]
[[Category: Ballaron, S.J.]]
[[Category: Haasch DL]]
[[Category: Haasch, D.L.]]
[[Category: Hajduk PJ]]
[[Category: Hajduk, P.J.]]
[[Category: Hutchins CW]]
[[Category: Hutchins, C.W.]]
[[Category: Jirousek MR]]
[[Category: Jirousek, M.R.]]
[[Category: Kaszubska W]]
[[Category: Kaszubska, W.]]
[[Category: Liu G]]
[[Category: Liu, G.]]
[[Category: Lubben TH]]
[[Category: Lubben, T.H.]]
[[Category: Pei Z]]
[[Category: Pei, Z.]]
[[Category: Rondinone CM]]
[[Category: Rondinone, C.M.]]
[[Category: Trevillyan JM]]
[[Category: Trevillyan, J.M.]]
[[Category: Xin Z]]
[[Category: Xin, Z.]]
[[Category: Zhao H]]
[[Category: Zhao, H.]]
[[Category: 234]]
[[Category: inhibitors with isoxazole-salicylate pharmacophores]]
[[Category: protein tyrosine phosphatase 1b]]
[[Category: ptp1b]]
 
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