9m2a: Difference between revisions

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'''Unreleased structure'''


The entry 9m2a is ON HOLD  until Paper Publication
==The crystal structure of the trypanosome alternative oxidase complexed with a trypanocidal phosphonium derivative (compound1)==
<StructureSection load='9m2a' size='340' side='right'caption='[[9m2a]], [[Resolution|resolution]] 3.01&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9m2a]] 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=9M2A OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9M2A 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]] 3.01&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1L8E:14-[diphenyl(pyridin-2-yl)-$l^{5}-phosphanyl]tetradecyl+2-methyl-4-oxidanyl-benzoate'>A1L8E</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=9m2a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9m2a OCA], [https://pdbe.org/9m2a PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9m2a RCSB], [https://www.ebi.ac.uk/pdbsum/9m2a PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9m2a 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., &gt;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 &gt;2300), it did not fully clear parasitemia in experimental animals, attributable to a high hepatic clearance.


Authors: Ebiloma, G.U., Balogun, E.O., Dardonville, C., De Koning, H.P., Shiba, T.
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>


Description: The crystal structure of the trypanosome alternative oxidase complexed with a trypanocidal phosphonium derivative (compound1)
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[Category: Unreleased Structures]]
</div>
[[Category: Balogun, E.O]]
<div class="pdbe-citations 9m2a" style="background-color:#fffaf0;"></div>
[[Category: De Koning, H.P]]
== References ==
[[Category: Shiba, T]]
<references/>
[[Category: Dardonville, C]]
__TOC__
[[Category: Ebiloma, G.U]]
</StructureSection>
[[Category: Large Structures]]
[[Category: Trypanosoma brucei brucei]]
[[Category: Balogun EO]]
[[Category: Dardonville C]]
[[Category: De Koning HP]]
[[Category: Ebiloma GU]]
[[Category: Shiba T]]
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