9kun: Difference between revisions
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New page: '''Unreleased structure''' The entry 9kun is ON HOLD Authors: Ebiloma, G.U., Balogun, E.O., Dardonville, C., Shiba, T., De Koning, H.P. Description: Crystal structure of ligand-free tr... |
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==Crystal structure of ligand-free trypanosome alternative oxidase== | |||
<StructureSection load='9kun' size='340' side='right'caption='[[9kun]], [[Resolution|resolution]] 2.70Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[9kun]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Trypanosoma_brucei_brucei Trypanosoma brucei brucei]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9KUN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9KUN 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]] 2.7Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BOG:B-OCTYLGLUCOSIDE'>BOG</scene>, <scene name='pdbligand=FE:FE+(III)+ION'>FE</scene>, <scene name='pdbligand=OH:HYDROXIDE+ION'>OH</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=9kun FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9kun OCA], [https://pdbe.org/9kun PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9kun RCSB], [https://www.ebi.ac.uk/pdbsum/9kun PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9kun ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/AOX_TRYBB AOX_TRYBB] Catalyzes cyanide-resistant oxygen consumption. May increase respiration when the cytochrome respiratory pathway is restricted, or in response to low temperatures. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The glucose-dependent respiration of bloodstream forms of the parasite Trypanosoma brucei depends on an unusual and essential mitochondrial electron-transport system, consisting of glycerol-3-phosphate dehydrogenase and the trypanosome alternative oxidase (TAO). We report here the discovery of an allosteric inhibitor of TAO that displays highly potent activity (EC(50) values in the range 1-20 nM) against the important veterinary pathogens T. b. brucei, Trypanosoma evansi, Trypanosoma equiperdum, and Trypanosoma congolense, i.e., >5-fold greater potency than the standard drugs. The methylene-linked 2-methyl-4-hydroxybenzoate 2-pyridinyldiphenylphosphonium derivative (1) was the best inhibitor of recombinant TAO (IC(50) = 1.3 nM) via a noncompetitive/allosteric mechanism (K(i) = 3.46 nM). Remarkably, X-ray crystallography showed that 1 was bound to a site of TAO approximately 25 A from the catalytic pocket. Although 1 demonstrated good safety toward mammalian cells in vitro (selectivity index >2300), it did not fully clear parasitemia in experimental animals, attributable to a high hepatic clearance. | |||
Uncovering the Unusual Inhibition Mechanism of a Trypanosome Alternative Oxidase Inhibitor Displaying Broad-Spectrum Activity against African Animal Trypanosomes.,Ebiloma GU, Balogun EO, Arai N, Otani M, Baldassarri C, Alhejely A, Cueto-Diaz E, De Koning HP, Dardonville C, Shiba T J Med Chem. 2025 Aug 28;68(16):17155-17174. doi: 10.1021/acs.jmedchem.5c00631. , Epub 2025 Jun 4. PMID:40464345<ref>PMID:40464345</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 9kun" style="background-color:#fffaf0;"></div> | ||
[[Category: | == References == | ||
[[Category: | <references/> | ||
[[Category: De Koning | __TOC__ | ||
[[Category: | </StructureSection> | ||
[[Category: Large Structures]] | |||
[[Category: Trypanosoma brucei brucei]] | |||
[[Category: Balogun EO]] | |||
[[Category: Dardonville C]] | |||
[[Category: De Koning HP]] | |||
[[Category: Ebiloma GU]] | |||
[[Category: Shiba T]] | |||
Latest revision as of 04:10, 14 September 2025
Crystal structure of ligand-free trypanosome alternative oxidase
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