View source for 1t31


==A Dual Inhibitor of the Leukocyte Proteases Cathepsin G and Chymase with Therapeutic Efficacy in Animals Models of Inflammation==
<StructureSection load='1t31' size='340' side='right'caption='[[1t31]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[1t31]] 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=1T31 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1T31 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]] 1.9&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CO:COBALT+(II)+ION'>CO</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=OHH:2-[3-({METHYL[1-(2-NAPHTHOYL)PIPERIDIN-4-YL]AMINO}CARBONYL)-2-NAPHTHYL]-1-(1-NAPHTHYL)-2-OXOETHYLPHOSPHONIC+ACID'>OHH</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=1t31 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1t31 OCA], [https://pdbe.org/1t31 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1t31 RCSB], [https://www.ebi.ac.uk/pdbsum/1t31 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1t31 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/CMA1_HUMAN CMA1_HUMAN] Major secreted protease of mast cells with suspected roles in vasoactive peptide generation, extracellular matrix degradation, and regulation of gland secretion.
== 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/t3/1t31_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=1t31 ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Certain leukocytes release serine proteases that sustain inflammatory processes and cause disease conditions, such as asthma and chronic obstructive pulmonary disease. We identified beta-ketophosphonate 1 (JNJ-10311795; RWJ-355871) as a novel, potent dual inhibitor of neutrophil cathepsin G (K(i) = 38 nm) and mast cell chymase (K(i) = 2.3 nm). The x-ray crystal structures of 1 complexed with human cathepsin G (1.85 A) and human chymase (1.90 A) reveal the molecular basis of the dual inhibition. Ligand 1 occupies the S(1) and S(2) subsites of cathepsin G and chymase similarly, with the 2-naphthyl in S(1), the 1-naphthyl in S(2), and the phosphonate group in a complex network of hydrogen bonds. Surprisingly, however, the carboxamido-N-(naphthalene-2-carboxyl)piperidine group is found to bind in two distinct conformations. In cathepsin G, this group occupies the hydrophobic S(3)/S(4) subsites, whereas in chymase, it does not; rather, it folds onto the 1-naphthyl group of the inhibitor itself. Compound 1 exhibited noteworthy anti-inflammatory activity in rats for glycogen-induced peritonitis and lipopolysaccharide-induced airway inflammation. In addition to a marked reduction in neutrophil influx, 1 reversed increases in inflammatory mediators interleukin-1alpha, interleukin-1beta, tissue necrosis factor-alpha, and monocyte chemotactic protein-1 in the glycogen model and reversed increases in airway nitric oxide levels in the lipopolysaccharide model. These findings demonstrate that it is possible to inhibit both cathepsin G and chymase with a single molecule and suggest an exciting opportunity in the treatment of asthma and chronic obstructive pulmonary disease.

A novel, potent dual inhibitor of the leukocyte proteases cathepsin G and chymase: molecular mechanisms and anti-inflammatory activity in vivo.,de Garavilla L, Greco MN, Sukumar N, Chen ZW, Pineda AO, Mathews FS, Di Cera E, Giardino EC, Wells GI, Haertlein BJ, Kauffman JA, Corcoran TW, Derian CK, Eckardt AJ, Damiano BP, Andrade-Gordon P, Maryanoff BE J Biol Chem. 2005 May 6;280(18):18001-7. Epub 2005 Feb 28. PMID:15741158<ref>PMID:15741158</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 1t31" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Abraham WM]]
[[Category: Andrade-Gordon P]]
[[Category: Bode W]]
[[Category: Chen Z]]
[[Category: Corcoran TW]]
[[Category: Damiano BP]]
[[Category: Derian CK]]
[[Category: Di Cera E]]
[[Category: Eckardt AJ]]
[[Category: Giardino EC]]
[[Category: Greco MN]]
[[Category: Haertlein BJ]]
[[Category: Huber R]]
[[Category: Kauffman JA]]
[[Category: Maryanoff BE]]
[[Category: Mathews FS]]
[[Category: Pereira PJB]]
[[Category: Pineda AO]]
[[Category: Rubin H]]
[[Category: Schechter NM]]
[[Category: Strobl S]]
[[Category: Sukumar N]]
[[Category: Wang ZM]]
[[Category: Wells GI]]
[[Category: De Garavilla L]]