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[[Image:1q6t.gif|left|200px]]


{{Structure
==THE STRUCTURE OF PHOSPHOTYROSINE PHOSPHATASE 1B IN COMPLEX WITH COMPOUND 11==
|PDB= 1q6t |SIZE=350|CAPTION= <scene name='initialview01'>1q6t</scene>, resolution 2.30&Aring;
<StructureSection load='1q6t' size='340' side='right'caption='[[1q6t]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
|SITE=  
== Structural highlights ==
|LIGAND= <scene name='pdbligand=600:6-[4-((2S)-2-(1H-1,2,3-BENZOTRIAZOL-1-YL)-3-{4-[DIFLUORO(PHOSPHONO)METHYL]PHENYL}-2-PHENYLPROPYL)PHENYL]-2-[(1S)-1-METHOXY-3-METHYLBUTYL]QUINOLIN-8-YLPHOSPHONIC+ACID'>600</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>
<table><tr><td colspan='2'>[[1q6t]] is a 2 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=1Q6T OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1Q6T FirstGlance]. <br>
|ACTIVITY= <span class='plainlinks'>[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] </span>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.3&#8491;</td></tr>
|GENE= PTPN1 OR PTP1B ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=600:6-[4-((2S)-2-(1H-1,2,3-BENZOTRIAZOL-1-YL)-3-{4-[DIFLUORO(PHOSPHONO)METHYL]PHENYL}-2-PHENYLPROPYL)PHENYL]-2-[(1S)-1-METHOXY-3-METHYLBUTYL]QUINOLIN-8-YLPHOSPHONIC+ACID'>600</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
|DOMAIN=
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1q6t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1q6t OCA], [https://pdbe.org/1q6t PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1q6t RCSB], [https://www.ebi.ac.uk/pdbsum/1q6t PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1q6t ProSAT]</span></td></tr>
|RELATEDENTRY=[[1q6j|1Q6J]], [[1q6m|1Q6M]], [[1q6n|1Q6N]], [[1q6p|1Q6P]], [[1q6s|1Q6S]]
</table>
|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1q6t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1q6t OCA], [http://www.ebi.ac.uk/pdbsum/1q6t PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1q6t RCSB]</span>
== 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/q6/1q6t_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=1q6t ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Protein tyrosine phosphatase 1B (PTP1B) has been implicated in the regulation of the insulin signaling pathway and represents an attractive target for the design of inhibitors in the treatment of type 2 diabetes and obesity. Inspection of the structure of PTP1B indicates that potent PTP1B inhibitors may be obtained by targeting a secondary aryl phosphate-binding site as well as the catalytic site. We report here the crystal structures of PTP1B in complex with first and second generation aryldifluoromethyl-phosphonic acid inhibitors. While all compounds bind in a previously unexploited binding pocket near the primary binding site, the second generation compounds also reach into the secondary binding site, and exhibit moderate selectivity for PTP1B over the closely related T-cell phosphatase. The molecular basis for the selectivity has been confirmed by single point mutation at position 52, where the two phosphatases differ by a phenylalanine-to-tyrosine switch. These compounds present a novel platform for the development of potent and selective PTP1B inhibitors.


'''THE STRUCTURE OF PHOSPHOTYROSINE PHOSPHATASE 1B IN COMPLEX WITH COMPOUND 11'''
The structural basis for the selectivity of benzotriazole inhibitors of PTP1B.,Scapin G, Patel SB, Becker JW, Wang Q, Desponts C, Waddleton D, Skorey K, Cromlish W, Bayly C, Therien M, Gauthier JY, Li CS, Lau CK, Ramachandran C, Kennedy BP, Asante-Appiah E Biochemistry. 2003 Oct 7;42(39):11451-9. PMID:14516196<ref>PMID:14516196</ref>


From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 1q6t" style="background-color:#fffaf0;"></div>


==Overview==
==See Also==
Protein tyrosine phosphatase 1B (PTP1B) has been implicated in the regulation of the insulin signaling pathway and represents an attractive target for the design of inhibitors in the treatment of type 2 diabetes and obesity. Inspection of the structure of PTP1B indicates that potent PTP1B inhibitors may be obtained by targeting a secondary aryl phosphate-binding site as well as the catalytic site. We report here the crystal structures of PTP1B in complex with first and second generation aryldifluoromethyl-phosphonic acid inhibitors. While all compounds bind in a previously unexploited binding pocket near the primary binding site, the second generation compounds also reach into the secondary binding site, and exhibit moderate selectivity for PTP1B over the closely related T-cell phosphatase. The molecular basis for the selectivity has been confirmed by single point mutation at position 52, where the two phosphatases differ by a phenylalanine-to-tyrosine switch. These compounds present a novel platform for the development of potent and selective PTP1B inhibitors.
*[[Tyrosine phosphatase 3D structures|Tyrosine phosphatase 3D structures]]
 
== References ==
==About this Structure==
<references/>
1Q6T is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1Q6T OCA].
__TOC__
 
</StructureSection>
==Reference==
The structural basis for the selectivity of benzotriazole inhibitors of PTP1B., Scapin G, Patel SB, Becker JW, Wang Q, Desponts C, Waddleton D, Skorey K, Cromlish W, Bayly C, Therien M, Gauthier JY, Li CS, Lau CK, Ramachandran C, Kennedy BP, Asante-Appiah E, Biochemistry. 2003 Oct 7;42(39):11451-9. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/14516196 14516196]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Protein-tyrosine-phosphatase]]
[[Category: Large Structures]]
[[Category: Single protein]]
[[Category: Asante-Appiah E]]
[[Category: Asante-Appiah, E.]]
[[Category: Bayly C]]
[[Category: Bayly, C.]]
[[Category: Becker JW]]
[[Category: Becker, J W.]]
[[Category: Cromlish W]]
[[Category: Cromlish, W.]]
[[Category: Desponts C]]
[[Category: Desponts, C.]]
[[Category: Gauthier JY]]
[[Category: Gauthier, J Y.]]
[[Category: Kennedy BP]]
[[Category: Kennedy, B P.]]
[[Category: Lau CK]]
[[Category: Lau, C K.]]
[[Category: Li CS]]
[[Category: Li, C S.]]
[[Category: Patel SB]]
[[Category: Patel, S B.]]
[[Category: Ramachandran C]]
[[Category: Ramachandran, C.]]
[[Category: Scapin G]]
[[Category: Scapin, G.]]
[[Category: Skorey K]]
[[Category: Skorey, K.]]
[[Category: Therien M]]
[[Category: Therien, M.]]
[[Category: Waddleton D]]
[[Category: Waddleton, D.]]
[[Category: Wang Q]]
[[Category: Wang, Q.]]
[[Category: phosphatase]]
[[Category: secondary binding site]]
[[Category: selectivity]]
 
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 30 23:09:35 2008''

Latest revision as of 12:58, 16 August 2023

THE STRUCTURE OF PHOSPHOTYROSINE PHOSPHATASE 1B IN COMPLEX WITH COMPOUND 11THE STRUCTURE OF PHOSPHOTYROSINE PHOSPHATASE 1B IN COMPLEX WITH COMPOUND 11

Structural highlights

1q6t is a 2 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 2.3Å
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.

Publication Abstract from PubMed

Protein tyrosine phosphatase 1B (PTP1B) has been implicated in the regulation of the insulin signaling pathway and represents an attractive target for the design of inhibitors in the treatment of type 2 diabetes and obesity. Inspection of the structure of PTP1B indicates that potent PTP1B inhibitors may be obtained by targeting a secondary aryl phosphate-binding site as well as the catalytic site. We report here the crystal structures of PTP1B in complex with first and second generation aryldifluoromethyl-phosphonic acid inhibitors. While all compounds bind in a previously unexploited binding pocket near the primary binding site, the second generation compounds also reach into the secondary binding site, and exhibit moderate selectivity for PTP1B over the closely related T-cell phosphatase. The molecular basis for the selectivity has been confirmed by single point mutation at position 52, where the two phosphatases differ by a phenylalanine-to-tyrosine switch. These compounds present a novel platform for the development of potent and selective PTP1B inhibitors.

The structural basis for the selectivity of benzotriazole inhibitors of PTP1B.,Scapin G, Patel SB, Becker JW, Wang Q, Desponts C, Waddleton D, Skorey K, Cromlish W, Bayly C, Therien M, Gauthier JY, Li CS, Lau CK, Ramachandran C, Kennedy BP, Asante-Appiah E Biochemistry. 2003 Oct 7;42(39):11451-9. PMID:14516196[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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
  3. ↑ Scapin G, Patel SB, Becker JW, Wang Q, Desponts C, Waddleton D, Skorey K, Cromlish W, Bayly C, Therien M, Gauthier JY, Li CS, Lau CK, Ramachandran C, Kennedy BP, Asante-Appiah E. The structural basis for the selectivity of benzotriazole inhibitors of PTP1B. Biochemistry. 2003 Oct 7;42(39):11451-9. PMID:14516196 doi:http://dx.doi.org/10.1021/bi035098j

1q6t, resolution 2.30Å

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