2za5

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(New page: 200px<br /><applet load="2za5" size="350" color="white" frame="true" align="right" spinBox="true" caption="2za5, resolution 2.300&Aring;" /> '''Crystal Structure o...)
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[[Image:2za5.jpg|left|200px]]<br /><applet load="2za5" size="350" color="white" frame="true" align="right" spinBox="true"
 
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caption="2za5, resolution 2.300&Aring;" />
 
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'''Crystal Structure of human tryptase with potent non-peptide inhibitor'''<br />
 
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==Overview==
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==Crystal Structure of human tryptase with potent non-peptide inhibitor==
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We have explored a series of spirocyclic piperidine amide derivatives (5) as tryptase inhibitors. Thus, 4 (JNJ-27390467) was identified as a potent, selective tryptase inhibitor with oral efficacy in two animal models of airway inflammation (sheep and guinea pig asthma models). An X-ray co-crystal structure of 4.tryptase revealed a hydrophobic pocket in the enzyme's active site, which is induced by the phenylethynyl group and is comprised of amino acid residues from two different monomers of the tetrameric protein.
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<StructureSection load='2za5' size='340' side='right'caption='[[2za5]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[2za5]] is a 4 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=2ZA5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2ZA5 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]] 2.3&#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=2FF:(5-(AMINOMETHYL)-2H-SPIRO[BENZOFURAN-3,4-PIPERIDINE]-1-YL)(5-(PHENYLETHYNYL)FURAN-2-YL)METHANONE'>2FF</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=2za5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2za5 OCA], [https://pdbe.org/2za5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2za5 RCSB], [https://www.ebi.ac.uk/pdbsum/2za5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2za5 ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/TRYB2_HUMAN TRYB2_HUMAN] Tryptase is the major neutral protease present in mast cells and is secreted upon the coupled activation-degranulation response of this cell type. Has an immunoprotective role during bacterial infection. Required to efficiently combat K.pneumoniae infection (By similarity).
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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/za/2za5_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.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=2za5 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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We have explored a series of spirocyclic piperidine amide derivatives (5) as tryptase inhibitors. Thus, 4 (JNJ-27390467) was identified as a potent, selective tryptase inhibitor with oral efficacy in two animal models of airway inflammation (sheep and guinea pig asthma models). An X-ray co-crystal structure of 4 x tryptase revealed a hydrophobic pocket in the enzyme's active site, which is induced by the phenylethynyl group and is comprised of amino acid residues from two different monomers of the tetrameric protein.
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==About this Structure==
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Potent, nonpeptide inhibitors of human mast cell tryptase. Synthesis and biological evaluation of novel spirocyclic piperidine amide derivatives.,Costanzo MJ, Yabut SC, Zhang HC, White KB, de Garavilla L, Wang Y, Minor LK, Tounge BA, Barnakov AN, Lewandowski F, Milligan C, Spurlino JC, Abraham WM, Boswell-Smith V, Page CP, Maryanoff BE Bioorg Med Chem Lett. 2008 Mar 15;18(6):2114-21. Epub 2008 Jan 30. PMID:18272363<ref>PMID:18272363</ref>
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2ZA5 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=2FF:'>2FF</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Tryptase Tryptase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.59 3.4.21.59] Known structural/functional Sites: <scene name='pdbsite=AC1:2ff+Binding+Site+For+Residue+B+1'>AC1</scene>, <scene name='pdbsite=AC2:2ff+Binding+Site+For+Residue+A+4'>AC2</scene>, <scene name='pdbsite=AC3:2ff+Binding+Site+For+Residue+D+3'>AC3</scene> and <scene name='pdbsite=AC4:2ff+Binding+Site+For+Residue+C+2'>AC4</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2ZA5 OCA].
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==Reference==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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Potent, nonpeptide inhibitors of human mast cell tryptase. Synthesis and biological evaluation of novel spirocyclic piperidine amide derivatives., Costanzo MJ, Yabut SC, Zhang HC, White KB, de Garavilla L, Wang Y, Minor LK, Tounge BA, Barnakov AN, Lewandowski F, Milligan C, Spurlino JC, Abraham WM, Boswell-Smith V, Page CP, Maryanoff BE, Bioorg Med Chem Lett. 2008 Jan 30;. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=18272363 18272363]
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</div>
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[[Category: Homo sapiens]]
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<div class="pdbe-citations 2za5" style="background-color:#fffaf0;"></div>
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[[Category: Single protein]]
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[[Category: Tryptase]]
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[[Category: Barnakov, S A.]]
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[[Category: Lewandowski, F.]]
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[[Category: Milligan, C.]]
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[[Category: Spurlino, J C.]]
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[[Category: 2FF]]
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[[Category: hydrolase]]
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[[Category: serine protease]]
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[[Category: tetramer]]
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[[Category: tryptase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Feb 27 07:59:29 2008''
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==See Also==
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*[[Tryptase|Tryptase]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Homo sapiens]]
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[[Category: Large Structures]]
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[[Category: Barnakov SA]]
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[[Category: Lewandowski F]]
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[[Category: Milligan C]]
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[[Category: Spurlino JC]]

Current revision

Crystal Structure of human tryptase with potent non-peptide inhibitor

PDB ID 2za5

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