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==Crystal structure of Plasmodium falciparum dihydroorotate dehydrogenase bound with novel Inhibitor Genz667348==
==Crystal structure of Plasmodium falciparum dihydroorotate dehydrogenase bound with novel Inhibitor Genz667348==
<StructureSection load='3o8a' size='340' side='right' caption='[[3o8a]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
<StructureSection load='3o8a' size='340' side='right'caption='[[3o8a]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[3o8a]] 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=3O8A OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3O8A FirstGlance]. <br>
<table><tr><td colspan='2'>[[3o8a]] 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=3O8A OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3O8A 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=LDA:LAURYL+DIMETHYLAMINE-N-OXIDE'>LDA</scene>, <scene name='pdbligand=O8A:N-CYCLOPROPYL-5-[2-METHYL-5-(TRIFLUOROMETHOXY)-1H-BENZIMIDAZOL-1-YL]THIOPHENE-2-CARBOXAMIDE'>O8A</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]] 2.3&#8491;</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">dihydroorotate dehydrogenase, PFF0160c ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=36329 PLAF7])</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=LDA:LAURYL+DIMETHYLAMINE-N-OXIDE'>LDA</scene>, <scene name='pdbligand=O8A:N-CYCLOPROPYL-5-[2-METHYL-5-(TRIFLUOROMETHOXY)-1H-BENZIMIDAZOL-1-YL]THIOPHENE-2-CARBOXAMIDE'>O8A</scene>, <scene name='pdbligand=ORO:OROTIC+ACID'>ORO</scene></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'>[https://proteopedia.org/fgij/fg.htm?mol=3o8a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3o8a OCA], [https://pdbe.org/3o8a PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3o8a RCSB], [https://www.ebi.ac.uk/pdbsum/3o8a PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3o8a ProSAT]</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=3o8a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3o8a OCA], [http://pdbe.org/3o8a PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3o8a RCSB], [http://www.ebi.ac.uk/pdbsum/3o8a PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3o8a 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.
== Evolutionary Conservation ==
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
Check<jmol>
   <jmolCheckbox>
   <jmolCheckbox>
     <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/o8/3o8a_consurf.spt"</scriptWhenChecked>
     <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/o8/3o8a_consurf.spt"</scriptWhenChecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
     <text>to colour the structure by Evolutionary Conservation</text>
     <text>to colour the structure by Evolutionary Conservation</text>
Line 21: Line 20:
</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=3o8a ConSurf].
</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=3o8a ConSurf].
<div style="clear:both"></div>
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Plasmodium falciparum, the causative agent of the most deadly form of human malaria, is unable to salvage pyrimidines and must rely on de novo biosynthesis for survival. Dihydroorotate dehydrogenase (DHODH) catalyzes the rate-limiting step in the pyrimidine biosynthetic pathway and represents a potential target for anti-malarial therapy. A high throughput screen and subsequent medicinal chemistry program identified a series of N-alkyl-5-(1H-benzimidazol-1-yl)thiophene-2-carboxamides with low nanomolar in vitro potency against DHODH from P. falciparum, P. vivax, and P. berghei. The compounds were selective for the parasite enzymes over human DHODH, and x-ray structural data on the analog Genz-667348, demonstrated that species selectivity could be attributed to amino acid differences in the inhibitor-binding site. Compounds from this series demonstrated in vitro potency against the 3D7 and Dd2 strains of P. falciparum, good tolerability and oral exposure in the mouse, and ED(50) values in the 4-day murine P. berghei efficacy model of 13-21 mg/kg/day with oral twice-daily dosing. In particular, treatment with Genz-667348 at 100 mg/kg/day resulted in sterile cure. Two recent analogs of Genz-667348 are currently undergoing pilot toxicity testing to determine suitability as clinical development candidates.


Novel inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase with anti-malarial activity in the mouse model.,Booker ML, Bastos CM, Kramer ML, Barker RH Jr, Skerlj R, Sidhu AB, Deng X, Celatka C, Cortese JF, Guerrero Bravo JE, Crespo Llado KN, Serrano AE, Angulo-Barturen I, Jimenez-Diaz MB, Viera S, Garuti H, Wittlin S, Papastogiannidis P, Lin JW, Janse CJ, Khan SM, Duraisingh M, Coleman B, Goldsmith EJ, Phillips MA, Munoz B, Wirth DF, Klinger JD, Wiegand R, Sybertz E J Biol Chem. 2010 Oct 22;285(43):33054-64. Epub 2010 Aug 11. PMID:20702404<ref>PMID:20702404</ref>
==See Also==
 
*[[Dihydroorotate dehydrogenase 3D structures|Dihydroorotate dehydrogenase 3D structures]]
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 3o8a" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Plaf7]]
[[Category: Large Structures]]
[[Category: Booker, M L]]
[[Category: Plasmodium falciparum 3D7]]
[[Category: Deng, X]]
[[Category: Booker ML]]
[[Category: Phillips, M A]]
[[Category: Deng X]]
[[Category: Alpha beta fold]]
[[Category: Phillips MA]]
[[Category: Dihydroorotate dehydrogenase]]
[[Category: Fad]]
[[Category: Flavoprotein]]
[[Category: Genz667348]]
[[Category: Mitochondrion inner membrane]]
[[Category: Oxidoreductase]]
[[Category: Pyrimidine biosynthesis]]
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