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| | <StructureSection load='6e0b' size='340' side='right'caption='[[6e0b]], [[Resolution|resolution]] 2.10Å' scene=''> | | <StructureSection load='6e0b' size='340' side='right'caption='[[6e0b]], [[Resolution|resolution]] 2.10Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6e0b]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Plaf7 Plaf7]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6E0B OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6E0B FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6e0b]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Plasmodium_falciparum_3D7 Plasmodium falciparum 3D7]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6E0B OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6E0B FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FMN:FLAVIN+MONONUCLEOTIDE'>FMN</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=JZ8:5-METHYL-7-(NAPHTHALEN-2-YLAMINO)-1H-[1,2,4]TRIAZOLO[1,5-A]PYRIMIDINE-3,8-DIIUM'>JZ8</scene>, <scene name='pdbligand=LDA:LAURYL+DIMETHYLAMINE-N-OXIDE'>LDA</scene>, <scene name='pdbligand=ORO:OROTIC+ACID'>ORO</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]] 2.099Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3i65|3i65]], [[3i6r|3i6r]], [[3i68|3i68]]</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=JZ8:5-METHYL-7-(NAPHTHALEN-2-YLAMINO)-1H-[1,2,4]TRIAZOLO[1,5-A]PYRIMIDINE-3,8-DIIUM'>JZ8</scene>, <scene name='pdbligand=LDA:LAURYL+DIMETHYLAMINE-N-OXIDE'>LDA</scene>, <scene name='pdbligand=ORO:OROTIC+ACID'>ORO</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PFF0160c ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=36329 PLAF7])</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=6e0b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6e0b OCA], [https://pdbe.org/6e0b PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6e0b RCSB], [https://www.ebi.ac.uk/pdbsum/6e0b PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6e0b ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Dihydroorotate_dehydrogenase_(quinone) Dihydroorotate dehydrogenase (quinone)], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.3.5.2 1.3.5.2] </span></td></tr>
| + | |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6e0b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6e0b OCA], [http://pdbe.org/6e0b PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6e0b RCSB], [http://www.ebi.ac.uk/pdbsum/6e0b PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6e0b ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/PYRD_PLAF7 PYRD_PLAF7]] Catalyzes the conversion of dihydroorotate to orotate with quinone as electron acceptor. | + | [https://www.uniprot.org/uniprot/PYRD_PLAF7 PYRD_PLAF7] Catalyzes the conversion of dihydroorotate to orotate with quinone as electron acceptor. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Plaf7]] | + | [[Category: Plasmodium falciparum 3D7]] |
| - | [[Category: Deng, X]] | + | [[Category: Deng X]] |
| - | [[Category: Phillips, M A]] | + | [[Category: Phillips MA]] |
| - | [[Category: Tomchick, D R]] | + | [[Category: Tomchick DR]] |
| - | [[Category: Dihydroorotate dehydrogenase]]
| + | |
| - | [[Category: Dsm1]]
| + | |
| - | [[Category: Fad]]
| + | |
| - | [[Category: Flavoprotein]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Membrane]]
| + | |
| - | [[Category: Mitochondrion]]
| + | |
| - | [[Category: Mitochondrion inner membrane]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
| - | [[Category: Plasmodium falciparum]]
| + | |
| - | [[Category: Pyrimidine biosynthesis]]
| + | |
| - | [[Category: Transit peptide]]
| + | |
| - | [[Category: Triazolopyrimidine]]
| + | |
| Structural highlights
6e0b is a 1 chain structure with sequence from Plasmodium falciparum 3D7. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 2.099Å |
| Ligands: | , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
PYRD_PLAF7 Catalyzes the conversion of dihydroorotate to orotate with quinone as electron acceptor.
Publication Abstract from PubMed
Malaria is one of the most challenging human infectious diseases, and both prevention and control have been hindered by the development of Plasmodium falciparum resistance to existing therapies. Several new compounds with novel mechanisms are in clinical development for the treatment of malaria, including DSM265, an inhibitor of Plasmodium dihydroorotate dehydrogenase. To explore the mechanisms by which resistance might develop to DSM265 in the field, we selected for DSM265-resistant P. falciparum parasites in vitro. Any of five different amino acid changes led to reduced efficacy on the parasite and to decreased DSM265 binding to P. falciparum DHODH. The DSM265-resistant parasites retained full sensitivity to atovaquone. All but one of the observed mutations were in the DSM265 binding site, and the remaining C276F was in the adjacent flavin cofactor site. The C276F mutation was previously identified in a recrudescent parasite during a Phase IIa clinical study. We confirmed that this mutation (and the related C276Y) accounted for the full level of observed DSM265 resistance by regenerating the mutation using CRISPR/Cas9 genome editing. X-ray structure analysis of the C276F mutant enzyme showed that conformational changes of nearby residues were required to accommodate the larger F276 residue, which in turn led to a restriction in the size of the DSM265 binding pocket. These findings underscore the importance of developing DSM265 as part of a combination therapy with other agents for successful use against malaria.
Identification and Mechanistic Understanding of Dihydroorotate Dehydrogenase Point Mutations in Plasmodium falciparum that Confer in Vitro Resistance to the Clinical Candidate DSM265.,White J, Dhingra SK, Deng X, El Mazouni F, Lee MCS, Afanador GA, Lawong A, Tomchick DR, Ng CL, Bath J, Rathod PK, Fidock DA, Phillips MA ACS Infect Dis. 2018 Nov 13. doi: 10.1021/acsinfecdis.8b00211. PMID:30375858[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ White J, Dhingra SK, Deng X, El Mazouni F, Lee MCS, Afanador GA, Lawong A, Tomchick DR, Ng CL, Bath J, Rathod PK, Fidock DA, Phillips MA. Identification and Mechanistic Understanding of Dihydroorotate Dehydrogenase Point Mutations in Plasmodium falciparum that Confer in Vitro Resistance to the Clinical Candidate DSM265. ACS Infect Dis. 2018 Nov 13. doi: 10.1021/acsinfecdis.8b00211. PMID:30375858 doi:http://dx.doi.org/10.1021/acsinfecdis.8b00211
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