1gxf: Difference between revisions

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

@@ Line 1: / Line 1: @@
-[[Image:1gxf.png|left|200px]]
-<!--
+==CRYSTAL STRUCTURE OF TRYPANOSOMA CRUZI TRYPANOTHIONE REDUCTASE IN COMPLEX WITH THE INHIBITOR QUINACRINE MUSTARD==
-The line below this paragraph, containing "STRUCTURE_1gxf", creates the "Structure Box" on the page.
+<StructureSection load='1gxf' size='340' side='right'caption='[[1gxf]], [[Resolution|resolution]] 2.70&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'>[[1gxf]] is a 2 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=1GXF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1GXF 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]] 2.7&#8491;</td></tr>
--->
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=MAE:MALEIC+ACID'>MAE</scene>, <scene name='pdbligand=QUM:QUINACRINE+MUSTARD'>QUM</scene></td></tr>
-{{STRUCTURE_1gxf|  PDB=1gxf  |  SCENE=  }}
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1gxf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1gxf OCA], [https://pdbe.org/1gxf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1gxf RCSB], [https://www.ebi.ac.uk/pdbsum/1gxf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1gxf ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/TYTR_TRYCR TYTR_TRYCR] Trypanothione is the parasite analog of glutathione; this enzyme is the equivalent of glutathione reductase.
+== 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/gx/1gxf_consurf.spt"</scriptWhenChecked>
+    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.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=1gxf ConSurf].
+<div style="clear:both"></div>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Trypanothione reductase is a key enzyme in the trypanothione-based redox metabolism of pathogenic trypanosomes. Because this system is absent in humans, being replaced with glutathione and glutathione reductase, it offers a target for selective inhibition. The rational design of potent inhibitors requires accurate structures of enzyme-inhibitor complexes, but this is lacking for trypanothione reductase. We therefore used quinacrine mustard, an alkylating derivative of the competitive inhibitor quinacrine, to probe the active site of this dimeric flavoprotein. Quinacrine mustard irreversibly inactivates Trypanosoma cruzi trypanothione reductase, but not human glutathione reductase, in a time-dependent manner with a stoichiometry of two inhibitors bound per monomer. The rate of inactivation is dependent upon the oxidation state of trypanothione reductase, with the NADPH-reduced form being inactivated significantly faster than the oxidized form. Inactivation is slowed by clomipramine and a melarsen oxide-trypanothione adduct (both are competitive inhibitors) but accelerated by quinacrine. The structure of the trypanothione reductase-quinacrine mustard adduct was determined to 2.7 A, revealing two molecules of inhibitor bound in the trypanothione-binding site. The acridine moieties interact with each other through pi-stacking effects, and one acridine interacts in a similar fashion with a tryptophan residue. These interactions provide a molecular explanation for the differing effects of clomipramine and quinacrine on inactivation by quinacrine mustard. Synergism with quinacrine occurs as a result of these planar acridines being able to stack together in the active site cleft, thereby gaining an increased number of binding interactions, whereas antagonism occurs with nonplanar molecules, such as clomipramine, where stacking is not possible.
-===CRYSTAL STRUCTURE OF TRYPANOSOMA CRUZI TRYPANOTHIONE REDUCTASE IN COMPLEX WITH THE INHIBITOR QUINACRINE MUSTARD===
+Two interacting binding sites for quinacrine derivatives in the active site of trypanothione reductase: a template for drug design.,Saravanamuthu A, Vickers TJ, Bond CS, Peterson MR, Hunter WN, Fairlamb AH J Biol Chem. 2004 Jul 9;279(28):29493-500. Epub 2004 Apr 21. PMID:15102853<ref>PMID:15102853</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-<!--
+</div>
-The line below this paragraph, {{ABSTRACT_PUBMED_15102853}}, adds the Publication Abstract to the page
+<div class="pdbe-citations 1gxf" style="background-color:#fffaf0;"></div>
-(as it appears on PubMed at http://www.pubmed.gov), where 15102853 is the PubMed ID number.
--->
-{{ABSTRACT_PUBMED_15102853}}
-==About this Structure==
-[[1gxf]] is a 2 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=1GXF OCA].
 ==See Also==
 *[[Trypanothione reductase|Trypanothione reductase]]
+== References ==
-==Reference==
+<references/>
-<ref group="xtra">PMID:015102853</ref><references group="xtra"/>
+__TOC__
+</StructureSection>
+[[Category: Large Structures]]
 [[Category: Trypanosoma cruzi]]
-[[Category: Trypanothione-disulfide reductase]]
+[[Category: Bond CS]]
-[[Category: Bond, C S.]]
+[[Category: Fairlamb AH]]
-[[Category: Fairlamb, A H.]]
+[[Category: Hunter WN]]
-[[Category: Hunter, W N.]]
+[[Category: Peterson MR]]
-[[Category: Peterson, M R.]]
+[[Category: Vickers TJ]]
-[[Category: Vickers, T J.]]
-[[Category: Disulphide oxidoreductase]]
-[[Category: Fad]]
-[[Category: Fad dependent]]
-[[Category: Flavoprotein]]
-[[Category: Inhibitor]]
-[[Category: Nadp]]
-[[Category: Oxidoreductase]]
-[[Category: Quinacrine mustard]]
-[[Category: Redox-active center]]
-[[Category: Trypanothione reductase]]