3iut: Difference between revisions

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-{{Seed}}
-[[Image:3iut.jpg|left|200px]]
-<!--
+==The Crystal Structure of Cruzain in Complex with a Tetrafluorophenoxymethyl Ketone Inhibitor==
-The line below this paragraph, containing "STRUCTURE_3iut", creates the "Structure Box" on the page.
+<StructureSection load='3iut' size='340' side='right'caption='[[3iut]], [[Resolution|resolution]] 1.20&Aring;' scene=''>
-You may change the PDB parameter (which sets the PDB file loaded into the applet)
+== Structural highlights ==
-or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
+<table><tr><td colspan='2'>[[3iut]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Trypanosoma_cruzi Trypanosoma cruzi]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3IUT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3IUT FirstGlance]. <br>
-or leave the SCENE parameter empty for the default display.
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.2&#8491;</td></tr>
--->
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=KB2:(3S)-3-(4-{(1S)-1,2-DIMETHYL-1-[(QUINOLIN-6-YLMETHYL)AMINO]PROPYL}-1H-1,2,3-TRIAZOL-1-YL)HEPTAN-2-ONE'>KB2</scene></td></tr>
-{{STRUCTURE_3iut|  PDB=3iut  |  SCENE=  }}
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3iut FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3iut OCA], [https://pdbe.org/3iut PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3iut RCSB], [https://www.ebi.ac.uk/pdbsum/3iut PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3iut ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/CYSP_TRYCR CYSP_TRYCR] Hydrolyzes chromogenic peptides at the carboxyl Arg or Lys; requires at least one more amino acid, preferably Arg, Phe, Val or Leu, between the terminal Arg or Lys and the amino-blocking group.  The cysteine protease may play an important role in the development and differentiation of the parasites at several stages of their life cycle.
+== 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/iu/3iut_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=3iut ConSurf].
+<div style="clear:both"></div>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+A century after discovering that the Trypanosoma cruzi parasite is the etiological agent of Chagas disease, treatment is still plagued by limited efficacy, toxicity, and the emergence of drug resistance. The development of inhibitors of the major T. cruzi cysteine protease, cruzain, has been demonstrated to be a promising drug discovery avenue for this neglected disease. Here we establish that a nonpeptidic tetrafluorophenoxymethyl ketone cruzain inhibitor substantially ameliorates symptoms of acute Chagas disease in a mouse model with no apparent toxicity. A high-resolution crystal structure confirmed the mode of inhibition and revealed key binding interactions of this novel inhibitor class. Subsequent structure-guided optimization then resulted in inhibitor analogues with improvements in potency despite minimal or no additions in molecular weight. Evaluation of the analogues in cell culture showed enhanced activity. These results suggest that nonpeptidic tetrafluorophenoxymethyl ketone cruzain inhibitors have the potential to fulfill the urgent need for improved Chagas disease chemotherapy.
-===The Crystal Structure of Cruzain in Complex with a Tetrafluorophenoxymethyl Ketone Inhibitor===
+Nonpeptidic tetrafluorophenoxymethyl ketone cruzain inhibitors as promising new leads for chagas disease chemotherapy.,Brak K, Kerr ID, Barrett KT, Fuchi N, Debnath M, Ang K, Engel JC, McKerrow JH, Doyle PS, Brinen LS, Ellman JA J Med Chem. 2010 Feb 25;53(4):1763-73. PMID:20088534<ref>PMID:20088534</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 3iut" style="background-color:#fffaf0;"></div>
-<!--
+==See Also==
-The line below this paragraph, {{ABSTRACT_PUBMED_20088534}}, adds the Publication Abstract to the page
+*[[Cruzain|Cruzain]]
-(as it appears on PubMed at http://www.pubmed.gov), where 20088534 is the PubMed ID number.
+== References ==
--->
+<references/>
-{{ABSTRACT_PUBMED_20088534}}
+__TOC__
+</StructureSection>
-==About this Structure==
+[[Category: Large Structures]]
-IUT is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Trypanosoma_cruzi Trypanosoma cruzi]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3IUT OCA].
-==Reference==
-<ref group="xtra">PMID:20088534</ref><references group="xtra"/>
-[[Category: Cruzipain]]
 [[Category: Trypanosoma cruzi]]
-[[Category: Brinen, L S.]]
+[[Category: Brinen LS]]
-[[Category: Debnath, M.]]
+[[Category: Debnath M]]
-[[Category: Kerr, I D.]]
+[[Category: Kerr ID]]
-[[Category: Autocatalytic cleavage]]
-[[Category: Disulfide bond]]
-[[Category: Glycoprotein]]
-[[Category: Hydrolase]]
-[[Category: Mature domain]]
-[[Category: Papain family cysteine protease]]
-[[Category: Protease]]
-[[Category: Thiol protease]]
-[[Category: Zymogen]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Mar  3 16:06:32 2010''