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1nc6

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(New page: 200px<br /><applet load="1nc6" size="450" color="white" frame="true" align="right" spinBox="true" caption="1nc6, resolution 1.90&Aring;" /> '''Potent, small molecu...)
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[[Image:1nc6.gif|left|200px]]<br /><applet load="1nc6" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="1nc6, resolution 1.90&Aring;" />
 
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'''Potent, small molecule inhibitors of human mast cell tryptase. Anti-asthmatic action of a dipeptide-based transition state analogue containing benzothiazole ketone'''<br />
 
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==Overview==
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==Potent, small molecule inhibitors of human mast cell tryptase. Anti-asthmatic action of a dipeptide-based transition state analogue containing benzothiazole ketone==
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Inhibitors of human mast cell tryptase (EC 3.4.21.59) have therapeutic, potential for treating allergic or inflammatory disorders. We have, investigated transition-state mimetics possessing a heterocycle-activated, ketone group and identified in particular benzothiazole ketone (2S)-6, (RWJ-56423) as a potent, reversible, low-molecular-weight tryptase, inhibitor with a K(i) value of 10 nM. A single-crystal X-ray analysis of, the sulfate salt of (2S)-6 confirmed the stereochemistry. Analogues 12 and, 15-17 are also potent tryptase inhibitors. Although RWJ-56423 potently, inhibits trypsin (K(i) = 8.1 nM), it is selective vs other serine, proteases, such as kallikrein, plasmin, and thrombin. We obtained an X-ray, structure of (2S)-6 complexed with bovine trypsin (1.9-A resolution), which depicts inter alia a hemiketal involving Ser-189, and hydrogen bonds, with His-57 and Gln-192. Aerosol administration of 6 (2R,2S; RWJ-58643) to, allergic sheep effectively antagonized antigen-induced asthmatic, responses, with 70-75% blockade of the early response and complete, ablation of the late response and airway hyperresponsiveness.
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<StructureSection load='1nc6' size='340' side='right'caption='[[1nc6]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1nc6]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Bos_taurus Bos taurus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1NC6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1NC6 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]] 1.9&#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=ABB:(2S,4R)-1-ACETYL-N-[(1S)-4-[(AMINOIMINOMETHYL)AMINO]-1-(2-BENZOTHIAZOLYLCARBONYL)BUTYL]-4-HYDROXY-2-PYRROLIDINECARBOXAMIDE'>ABB</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=1nc6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1nc6 OCA], [https://pdbe.org/1nc6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1nc6 RCSB], [https://www.ebi.ac.uk/pdbsum/1nc6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1nc6 ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/TRY1_BOVIN TRY1_BOVIN]
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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/nc/1nc6_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=1nc6 ConSurf].
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<div style="clear:both"></div>
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==About this Structure==
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==See Also==
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1NC6 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Bos_taurus Bos taurus] with CA, SO4 and ABB as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Trypsin Trypsin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.4 3.4.21.4] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1NC6 OCA].
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*[[Trypsin 3D structures|Trypsin 3D structures]]
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__TOC__
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==Reference==
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</StructureSection>
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Potent, small-molecule inhibitors of human mast cell tryptase. Antiasthmatic action of a dipeptide-based transition-state analogue containing a benzothiazole ketone., Costanzo MJ, Yabut SC, Almond HR Jr, Andrade-Gordon P, Corcoran TW, De Garavilla L, Kauffman JA, Abraham WM, Recacha R, Chattopadhyay D, Maryanoff BE, J Med Chem. 2003 Aug 28;46(18):3865-76. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=12930148 12930148]
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[[Category: Bos taurus]]
[[Category: Bos taurus]]
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[[Category: Single protein]]
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[[Category: Large Structures]]
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[[Category: Trypsin]]
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[[Category: Abraham WM]]
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[[Category: Abraham, W.M.]]
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[[Category: Almond Jr HR]]
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[[Category: Andrade-Gordon, P.]]
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[[Category: Andrade-Gordon P]]
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[[Category: Chattopadhyay, D.]]
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[[Category: Chattopadhyay D]]
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[[Category: Corcoran, T.W.]]
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[[Category: Corcoran TW]]
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[[Category: Costanzo, M.J.]]
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[[Category: Costanzo MJ]]
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[[Category: Garavilla, L.de.]]
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[[Category: Kauffman JA]]
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[[Category: Jr., H.R.Almond.]]
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[[Category: Maryanoff BE]]
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[[Category: Kauffman, J.A.]]
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[[Category: Recacha R]]
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[[Category: Maryanoff, B.E.]]
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[[Category: Yabut SC]]
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[[Category: Recacha, R.]]
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[[Category: De Garavilla L]]
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[[Category: Yabut, S.C.]]
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[[Category: ABB]]
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[[Category: CA]]
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[[Category: SO4]]
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[[Category: protein-inhibitor complex]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Tue Nov 20 22:07:51 2007''
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Current revision

Potent, small molecule inhibitors of human mast cell tryptase. Anti-asthmatic action of a dipeptide-based transition state analogue containing benzothiazole ketone

PDB ID 1nc6

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