1nc6
From Proteopedia
(Difference between revisions)
| (15 intermediate revisions not shown.) | |||
| Line 1: | Line 1: | ||
| - | [[Image:1nc6.gif|left|200px]]<br /><applet load="1nc6" size="350" color="white" frame="true" align="right" spinBox="true" | ||
| - | caption="1nc6, resolution 1.90Å" /> | ||
| - | '''Potent, small molecule inhibitors of human mast cell tryptase. Anti-asthmatic action of a dipeptide-based transition state analogue containing benzothiazole ketone'''<br /> | ||
| - | == | + | ==Potent, small molecule inhibitors of human mast cell tryptase. Anti-asthmatic action of a dipeptide-based transition state analogue containing benzothiazole ketone== |
| + | <StructureSection load='1nc6' size='340' side='right'caption='[[1nc6]], [[Resolution|resolution]] 1.90Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <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> | ||
| + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.9Å</td></tr> | ||
| + | <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> | ||
| + | <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> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/TRY1_BOVIN TRY1_BOVIN] | ||
| + | == 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/nc/1nc6_consurf.spt"</scriptWhenChecked> | ||
| + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.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=1nc6 ConSurf]. | ||
| + | <div style="clear:both"></div> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
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. | 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. | ||
| - | + | 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:12930148<ref>PMID:12930148</ref> | |
| - | + | ||
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
| - | + | <div class="pdbe-citations 1nc6" style="background-color:#fffaf0;"></div> | |
| - | + | ||
| - | + | ||
| - | + | ||
| - | + | ||
| - | + | ||
| - | + | ||
| - | + | ||
| - | + | ||
| - | + | ||
| - | + | ||
| - | + | ||
| - | + | ||
| - | + | ||
| - | + | ||
| - | + | ||
| - | + | ||
| - | + | ||
| - | + | ==See Also== | |
| + | *[[Trypsin 3D structures|Trypsin 3D structures]] | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Bos taurus]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Abraham WM]] | ||
| + | [[Category: Almond Jr HR]] | ||
| + | [[Category: Andrade-Gordon P]] | ||
| + | [[Category: Chattopadhyay D]] | ||
| + | [[Category: Corcoran TW]] | ||
| + | [[Category: Costanzo MJ]] | ||
| + | [[Category: Kauffman JA]] | ||
| + | [[Category: Maryanoff BE]] | ||
| + | [[Category: Recacha R]] | ||
| + | [[Category: Yabut SC]] | ||
| + | [[Category: De Garavilla L]] | ||
Current revision
Potent, small molecule inhibitors of human mast cell tryptase. Anti-asthmatic action of a dipeptide-based transition state analogue containing benzothiazole ketone
| |||||||||||
