2nt7

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(New page: 200px<br /> <applet load="2nt7" size="450" color="white" frame="true" align="right" spinBox="true" caption="2nt7, resolution 2.1&Aring;" /> '''Crystal structure of...)
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[[Image:2nt7.gif|left|200px]]<br />
 
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<applet load="2nt7" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="2nt7, resolution 2.1&Aring;" />
 
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'''Crystal structure of PTP1B-inhibitor complex'''<br />
 
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==Overview==
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==Crystal structure of PTP1B-inhibitor complex==
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The following account describes our systematic effort to replace one of, the carboxylate groups of our diacid thiophene PTP1B inhibitors. Active, hits were validated using enzymatic assays before pursuing efforts to, improve the potency. Only when the C2 carboxylic acid was replaced with, another ionizable functional group was reversible and competitive, inhibition retained. Use of a tetrazole ring or, 1,2,5-thiadiazolidine-3-one-1,1-dioxide as a carboxylate mimetic led to, the discovery of two unique starting series that showed improved, permeability (PAMPA) and potency of the order of 300nM. The SAR from these, efforts underscores some of the major challenges in developing small, molecule inhibitors for PTP1B.
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<StructureSection load='2nt7' size='340' side='right'caption='[[2nt7]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[2nt7]] 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=2NT7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2NT7 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]] 2.1&#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=902:{[5-(3-{[1-(BENZYLSULFONYL)PIPERIDIN-4-YL]AMINO}PHENYL)-4-BROMO-2-(2H-TETRAZOL-5-YL)-3-THIENYL]OXY}ACETIC+ACID'>902</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=2nt7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2nt7 OCA], [https://pdbe.org/2nt7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2nt7 RCSB], [https://www.ebi.ac.uk/pdbsum/2nt7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2nt7 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/nt/2nt7_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=2nt7 ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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The following account describes our systematic effort to replace one of the carboxylate groups of our diacid thiophene PTP1B inhibitors. Active hits were validated using enzymatic assays before pursuing efforts to improve the potency. Only when the C2 carboxylic acid was replaced with another ionizable functional group was reversible and competitive inhibition retained. Use of a tetrazole ring or 1,2,5-thiadiazolidine-3-one-1,1-dioxide as a carboxylate mimetic led to the discovery of two unique starting series that showed improved permeability (PAMPA) and potency of the order of 300nM. The SAR from these efforts underscores some of the major challenges in developing small molecule inhibitors for PTP1B.
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==Disease==
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Probing acid replacements of thiophene PTP1B inhibitors.,Wan ZK, Follows B, Kirincich S, Wilson D, Binnun E, Xu W, Joseph-McCarthy D, Wu J, Smith M, Zhang YL, Tam M, Erbe D, Tam S, Saiah E, Lee J Bioorg Med Chem Lett. 2007 May 15;17(10):2913-20. Epub 2007 Feb 20. PMID:17336064<ref>PMID:17336064</ref>
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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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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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2NT7 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 902 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=2NT7 OCA].
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</div>
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<div class="pdbe-citations 2nt7" style="background-color:#fffaf0;"></div>
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==Reference==
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==See Also==
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Probing acid replacements of thiophene PTP1B inhibitors., Wan ZK, Follows B, Kirincich S, Wilson D, Binnun E, Xu W, Joseph-McCarthy D, Wu J, Smith M, Zhang YL, Tam M, Erbe D, Tam S, Saiah E, Lee J, Bioorg Med Chem Lett. 2007 Feb 20;. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17336064 17336064]
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*[[Tyrosine phosphatase 3D structures|Tyrosine phosphatase 3D structures]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
[[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: Follows B]]
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[[Category: Follows, B.]]
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[[Category: Xu W]]
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[[Category: Xu, W.]]
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[[Category: 902]]
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[[Category: protein-inhibitor complex]]
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[[Category: ptp1b]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 23:02:39 2007''
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Current revision

Crystal structure of PTP1B-inhibitor complex

PDB ID 2nt7

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OCA

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