1wax

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[[Image:1wax.gif|left|200px]]<br /><applet load="1wax" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="1wax, resolution 2.20&Aring;" />
 
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'''PROTEIN TYROSINE PHOSPHATASE 1B WITH ACTIVE SITE INHIBITOR'''<br />
 
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==Overview==
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==Protein tyrosine phosphatase 1B with active site inhibitor==
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Fragment screening offers an alternative to traditional screening for, discovering new leads in drug discovery programs. This paper describes a, fragment screening methodology based on high throughput X-ray, crystallography. The method is illustrated against five proteins (p38 MAP, kinase, CDK2, thrombin, ribonuclease A, and PTP1B). The fragments, identified have weak potency (&gt;100 microM) but are efficient binders, relative to their size and may therefore represent suitable starting, points for evolution to good quality lead compounds. The examples, illustrate that a range of molecular interactions (i.e., lipophilic, charge-charge, neutral hydrogen bonds) can drive fragment binding and also, that fragments can induce protein movement. We believe that the method has, great potential for the discovery of novel lead compounds against a range, of targets, and the companion paper illustrates how lead compounds have, been identified for p38 MAP kinase starting from fragments such as those, described in this paper.
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<StructureSection load='1wax' size='340' side='right'caption='[[1wax]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1wax]] 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=1WAX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1WAX 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]] 2.2&#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=LO1:[[4-(AMINOMETHYL)PHENYL]AMINO]OXO-ACETIC+ACID,'>LO1</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=1wax FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1wax OCA], [https://pdbe.org/1wax PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1wax RCSB], [https://www.ebi.ac.uk/pdbsum/1wax PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1wax 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/wa/1wax_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=1wax 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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Fragment screening offers an alternative to traditional screening for discovering new leads in drug discovery programs. This paper describes a fragment screening methodology based on high throughput X-ray crystallography. The method is illustrated against five proteins (p38 MAP kinase, CDK2, thrombin, ribonuclease A, and PTP1B). The fragments identified have weak potency (&gt;100 microM) but are efficient binders relative to their size and may therefore represent suitable starting points for evolution to good quality lead compounds. The examples illustrate that a range of molecular interactions (i.e., lipophilic, charge-charge, neutral hydrogen bonds) can drive fragment binding and also that fragments can induce protein movement. We believe that the method has great potential for the discovery of novel lead compounds against a range of targets, and the companion paper illustrates how lead compounds have been identified for p38 MAP kinase starting from fragments such as those described in this paper.
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==Disease==
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Fragment-based lead discovery using X-ray crystallography.,Hartshorn MJ, Murray CW, Cleasby A, Frederickson M, Tickle IJ, Jhoti H J Med Chem. 2005 Jan 27;48(2):403-13. PMID:15658854<ref>PMID:15658854</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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1WAX 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 MG and LO1 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] Known structural/functional Site: <scene name='pdbsite=AC1:Lo1 Binding Site For Chain A'>AC1</scene>. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1WAX OCA].
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</div>
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<div class="pdbe-citations 1wax" style="background-color:#fffaf0;"></div>
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==Reference==
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==See Also==
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Fragment-based lead discovery using X-ray crystallography., Hartshorn MJ, Murray CW, Cleasby A, Frederickson M, Tickle IJ, Jhoti H, J Med Chem. 2005 Jan 27;48(2):403-13. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=15658854 15658854]
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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: Cleasby A]]
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[[Category: Cleasby, A.]]
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[[Category: Frederickson M]]
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[[Category: Frederickson, M.]]
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[[Category: Hartshorn MJ]]
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[[Category: Hartshorn, M.J.]]
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[[Category: Jhoti H]]
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[[Category: Jhoti, H.]]
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[[Category: Murray CW]]
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[[Category: Murray, C.W.]]
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[[Category: Tickle IJ]]
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[[Category: Tickle, I.J.]]
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[[Category: LO1]]
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[[Category: MG]]
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[[Category: acetylation]]
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[[Category: hydrolase]]
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[[Category: inhibitors]]
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[[Category: phosphorylation]]
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[[Category: protein tyrosine phosphatase]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Tue Dec 18 18:36:33 2007''
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Current revision

Protein tyrosine phosphatase 1B with active site inhibitor

PDB ID 1wax

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