View source for 3i65


==Plasmodium falciparum dihydroorotate dehydrogenase bound with triazolopyrimidine-based inhibitor DSM1==
<StructureSection load='3i65' size='340' side='right'caption='[[3i65]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[3i65]] 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=3I65 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3I65 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&#8491;</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=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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3i65 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3i65 OCA], [https://pdbe.org/3i65 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3i65 RCSB], [https://www.ebi.ac.uk/pdbsum/3i65 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3i65 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/PYRD_PLAF7 PYRD_PLAF7] Catalyzes the conversion of dihydroorotate to orotate with quinone as electron acceptor.
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/i6/3i65_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</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=3i65 ConSurf].
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== Publication Abstract from PubMed ==
Malaria remains a major global health burden and current drug therapies are compromised by resistance. Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) was validated as a new drug target through the identification of potent and selective triazolopyrimidine-based DHODH inhibitors with anti-malarial activity in vivo. Here we report x-ray structure determination of PfDHODH bound to three inhibitors from this series, representing the first of the enzyme bound to malaria specific inhibitors. We demonstrate that conformational flexibility results in an unexpected binding mode identifying a new hydrophobic pocket on the enzyme. Importantly this plasticity allows PfDHODH to bind inhibitors from different chemical classes and to accommodate inhibitor modifications during lead optimization, increasing the value of PfDHODH as a drug target. A second discovery, based on small molecule crystallography, is that the triazolopyrimidines populate a resonance form that promotes charge separation. These intrinsic dipoles allow formation of energetically favorable H-bond interactions with the enzyme. The importance of delocalization to binding affinity was supported by site-directed mutagenesis and the demonstration that triazolopyrimidine analogs that lack this intrinsic dipole are inactive. Finally, the PfDHODH-triazolopyrimidine bound structures provide considerable new insight into species-selective inhibitor binding in this enzyme family. Together, these studies will directly impact efforts to exploit PfDHODH for the development of anti-malarial chemotherapy.

Structural plasticity of malaria dihydroorotate dehydrogenase allows selective binding of diverse chemical scaffolds.,Deng X, Gujjar R, El Mazouni F, Kaminsky W, Malmquist NA, Goldsmith EJ, Rathod PK, Phillips MA J Biol Chem. 2009 Sep 25;284(39):26999-7009. Epub 2009 Jul 28. PMID:19640844<ref>PMID:19640844</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 3i65" style="background-color:#fffaf0;"></div>

==See Also==
*[[Dihydroorotate dehydrogenase 3D structures|Dihydroorotate dehydrogenase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Plasmodium falciparum 3D7]]
[[Category: Deng X]]
[[Category: Phillips MA]]