1bzl: Difference between revisions
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< | ==CRYSTAL STRUCTURE OF TRYPANOSOMA CRUZI TRYPANOTHIONE REDUCTASE IN COMPLEX WITH TRYPANOTHIONE, AND THE STRUCTURE-BASED DISCOVERY OF NEW NATURAL PRODUCT INHIBITORS== | ||
<StructureSection load='1bzl' size='340' side='right'caption='[[1bzl]], [[Resolution|resolution]] 2.40Å' scene=''> | |||
You may | == Structural highlights == | ||
<table><tr><td colspan='2'>[[1bzl]] 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=1BZL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1BZL 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]] 2.4Å</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=GCG:BIS(GAMMA-GLUTAMYL-CYSTEINYL-GLYCINYL)SPERMIDINE'>GCG</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=1bzl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1bzl OCA], [https://pdbe.org/1bzl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1bzl RCSB], [https://www.ebi.ac.uk/pdbsum/1bzl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1bzl 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/bz/1bzl_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=1bzl ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
BACKGROUND: Trypanothione reductase (TR) helps to maintain an intracellular reducing environment in trypanosomatids, a group of protozoan parasites that afflict humans and livestock in tropical areas. This protective function is achieved via reduction of polyamine-glutathione conjugates, in particular trypanothione. TR has been validated as a chemotherapeutic target by molecular genetics methods. To assist the development of new therapeutics, we have characterised the structure of TR from the pathogen Trypanosoma cruzi complexed with the substrate trypanothione and have used the structure to guide database searches and molecular modelling studies. RESULTS: The TR-trypanothione-disulfide structure has been determined to 2.4 A resolution. The chemical interactions involved in enzyme recognition and binding of substrate can be inferred from this structure. Comparisons with the related mammalian enzyme, glutathione reductase, explain why each enzyme is so specific for its own substrate. A CH***O hydrogen bond can occur between the active-site histidine and a carbonyl of the substrate. This interaction contributes to enzyme specificity and mechanism by producing an electronic induced fit when substrate binds. Database searches and molecular modelling using the substrate as a template and the active site as receptor have identified a class of cyclic-polyamine natural products that are novel TR inhibitors. CONCLUSIONS: The structure of the TR-trypanothione enzyme-substrate complex provides details of a potentially valuable drug target. This information has helped to identify a new class of enzyme inhibitors as novel lead compounds worthy of further development in the search for improved medicines to treat a range of parasitic infections. | |||
Crystal structure of Trypanosoma cruzi trypanothione reductase in complex with trypanothione, and the structure-based discovery of new natural product inhibitors.,Bond CS, Zhang Y, Berriman M, Cunningham ML, Fairlamb AH, Hunter WN Structure. 1999 Jan 15;7(1):81-9. PMID:10368274<ref>PMID:10368274</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 1bzl" style="background-color:#fffaf0;"></div> | |||
== | |||
==See Also== | ==See Also== | ||
*[[Trypanothione reductase|Trypanothione reductase]] | *[[Trypanothione reductase|Trypanothione reductase]] | ||
== References == | |||
== | <references/> | ||
< | __TOC__ | ||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Trypanosoma cruzi]] | [[Category: Trypanosoma cruzi]] | ||
[[Category: Berriman M]] | |||
[[Category: Berriman | [[Category: Bond CS]] | ||
[[Category: Bond | [[Category: Cunningham M]] | ||
[[Category: Cunningham | [[Category: Fairlamb AH]] | ||
[[Category: Fairlamb | [[Category: Hunter WN]] | ||
[[Category: Hunter | [[Category: Zhang Y]] | ||
[[Category: Zhang | |||
Latest revision as of 07:25, 17 October 2024
CRYSTAL STRUCTURE OF TRYPANOSOMA CRUZI TRYPANOTHIONE REDUCTASE IN COMPLEX WITH TRYPANOTHIONE, AND THE STRUCTURE-BASED DISCOVERY OF NEW NATURAL PRODUCT INHIBITORSCRYSTAL STRUCTURE OF TRYPANOSOMA CRUZI TRYPANOTHIONE REDUCTASE IN COMPLEX WITH TRYPANOTHIONE, AND THE STRUCTURE-BASED DISCOVERY OF NEW NATURAL PRODUCT INHIBITORS
Structural highlights
FunctionTYTR_TRYCR Trypanothione is the parasite analog of glutathione; this enzyme is the equivalent of glutathione reductase. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedBACKGROUND: Trypanothione reductase (TR) helps to maintain an intracellular reducing environment in trypanosomatids, a group of protozoan parasites that afflict humans and livestock in tropical areas. This protective function is achieved via reduction of polyamine-glutathione conjugates, in particular trypanothione. TR has been validated as a chemotherapeutic target by molecular genetics methods. To assist the development of new therapeutics, we have characterised the structure of TR from the pathogen Trypanosoma cruzi complexed with the substrate trypanothione and have used the structure to guide database searches and molecular modelling studies. RESULTS: The TR-trypanothione-disulfide structure has been determined to 2.4 A resolution. The chemical interactions involved in enzyme recognition and binding of substrate can be inferred from this structure. Comparisons with the related mammalian enzyme, glutathione reductase, explain why each enzyme is so specific for its own substrate. A CH***O hydrogen bond can occur between the active-site histidine and a carbonyl of the substrate. This interaction contributes to enzyme specificity and mechanism by producing an electronic induced fit when substrate binds. Database searches and molecular modelling using the substrate as a template and the active site as receptor have identified a class of cyclic-polyamine natural products that are novel TR inhibitors. CONCLUSIONS: The structure of the TR-trypanothione enzyme-substrate complex provides details of a potentially valuable drug target. This information has helped to identify a new class of enzyme inhibitors as novel lead compounds worthy of further development in the search for improved medicines to treat a range of parasitic infections. Crystal structure of Trypanosoma cruzi trypanothione reductase in complex with trypanothione, and the structure-based discovery of new natural product inhibitors.,Bond CS, Zhang Y, Berriman M, Cunningham ML, Fairlamb AH, Hunter WN Structure. 1999 Jan 15;7(1):81-9. PMID:10368274[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences |
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