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| | <StructureSection load='6uy4' size='340' side='right'caption='[[6uy4]], [[Resolution|resolution]] 2.80Å' scene=''> | | <StructureSection load='6uy4' size='340' side='right'caption='[[6uy4]], [[Resolution|resolution]] 2.80Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6uy4]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Blood_fluke Blood fluke]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6UY4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6UY4 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6uy4]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Schistosoma_mansoni Schistosoma mansoni]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6UY4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6UY4 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FMN:FLAVIN+MONONUCLEOTIDE'>FMN</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=QLA:2-[(4-fluorophenyl)amino]-3-hydroxynaphthalene-1,4-dione'>QLA</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.796Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[6uoy|6uoy]]</div></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FMN:FLAVIN+MONONUCLEOTIDE'>FMN</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=QLA:2-[(4-fluorophenyl)amino]-3-hydroxynaphthalene-1,4-dione'>QLA</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Smp_078730 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=6183 Blood fluke])</td></tr>
| + | |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Dihydroorotate_oxidase_(fumarate) Dihydroorotate oxidase (fumarate)], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.3.98.1 1.3.98.1] </span></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=6uy4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6uy4 OCA], [https://pdbe.org/6uy4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6uy4 RCSB], [https://www.ebi.ac.uk/pdbsum/6uy4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6uy4 ProSAT]</span></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=6uy4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6uy4 OCA], [https://pdbe.org/6uy4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6uy4 RCSB], [https://www.ebi.ac.uk/pdbsum/6uy4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6uy4 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/G4VFD7_SCHMA G4VFD7_SCHMA] |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Blood fluke]] | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Mori, R M]] | |
| - | [[Category: Nonato, M C]] | |
| - | [[Category: Zapata, L C.C]] | |
| - | [[Category: Class 2 dihydroorotate dehydrogenase]] | |
| - | [[Category: Flavoprotein]] | |
| - | [[Category: Oxidoreductase-inhibitor complex]] | |
| | [[Category: Schistosoma mansoni]] | | [[Category: Schistosoma mansoni]] |
| - | [[Category: Smdhodh]] | + | [[Category: Mori RM]] |
| | + | [[Category: Nonato MC]] |
| | + | [[Category: Zapata LCC]] |
| Structural highlights
Function
G4VFD7_SCHMA
Publication Abstract from PubMed
Schistosomiasis is a serious public health problem, prevalent in tropical and subtropical areas, especially in poor communities without access to safe drinking water and adequate sanitation. Transmission has been reported in 78 countries and its control depends on a single drug, praziquantel, which has been used over the past 30 years. Our work is focused on exploiting target-based drug discovery strategies to develop new therapeutics to treat schistosomiasis. In particular, we are interested in evaluating the enzyme dihydroorotate dehydrogenase (DHODH) as a drug target. DHODH is a flavoenzyme that catalyzes the stereospecific oxidation of (S)-dihydroorotate (DHO) to orotate during the fourth and only redox step of the de novo pyrimidine nucleotide biosynthetic pathway. Previously, we identified atovaquone, used in the treatment of malaria, and its analogues, as potent and selective inhibitors against Schistosoma mansoni DHODH (SmDHODH). In the present article, we report the first crystal structure of SmDHODH in complex with the atovaquone-analog inhibitor 2-((4-fluorophenyl)amino)-3-hydroxynaphthalene-1,4-dione (QLA). We discuss three major findings: 1) the open conformation of the active site-loop and the unveiling of a novel transient druggable pocket for class 2 DHODHs; 2) The presence of a protuberant domain, only present in Schistosoma spp DHODHs, that was found to control and modulate the dynamics of the inhibitor binding site; 3) a detailed description of an unexpected binding mode for the atovaquone analogue to SmDHODH. Our findings contribute to the understanding of the catalytic mechanism performed by class 2 DHODHs, and provides the molecular basis for structure-guided design of SmDHODH inhibitors.
Structural basis for the function and inhibition of dihydroorotate dehydrogenase from Schistosoma mansoni.,Mori RM, Aleixo MAA, Zapata LCC, Calil FA, Emery FDS, Nonato MC FEBS J. 2020 May 19. doi: 10.1111/febs.15367. PMID:32428996[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Mori RM, Aleixo MAA, Zapata LCC, Calil FA, Emery FDS, Nonato MC. Structural basis for the function and inhibition of dihydroorotate dehydrogenase from Schistosoma mansoni. FEBS J. 2020 May 19. doi: 10.1111/febs.15367. PMID:32428996 doi:http://dx.doi.org/10.1111/febs.15367
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