6lp6: Difference between revisions
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==Crystal structure of human DHODH in complex with inhibitor 1214== | ==Crystal structure of human DHODH in complex with inhibitor 1214== | ||
<StructureSection load='6lp6' size='340' side='right'caption='[[6lp6]]' scene=''> | <StructureSection load='6lp6' size='340' side='right'caption='[[6lp6]], [[Resolution|resolution]] 1.79Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6LP6 OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[6lp6]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6LP6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6LP6 FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.795Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=B6U:3-[3,5-bis(fluoranyl)-4-[2-fluoranyl-5-(hydroxymethyl)phenyl]phenyl]benzo[f]benzotriazole-4,9-dione'>B6U</scene>, <scene name='pdbligand=FMN:FLAVIN+MONONUCLEOTIDE'>FMN</scene>, <scene name='pdbligand=LDA:LAURYL+DIMETHYLAMINE-N-OXIDE'>LDA</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=ORO:OROTIC+ACID'>ORO</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=6lp6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6lp6 OCA], [https://pdbe.org/6lp6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6lp6 RCSB], [https://www.ebi.ac.uk/pdbsum/6lp6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6lp6 ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Disease == | |||
[https://www.uniprot.org/uniprot/PYRD_HUMAN PYRD_HUMAN] Defects in DHODH are the cause of postaxial acrofacial dysostosis (POADS) [MIM:[https://omim.org/entry/263750 263750]; also known as Miller syndrome. POADS is characterized by severe micrognathia, cleft lip and/or palate, hypoplasia or aplasia of the posterior elements of the limbs, coloboma of the eyelids and supernumerary nipples. POADS is a very rare disorder: only 2 multiplex families, each consisting of 2 affected siblings born to unaffected, nonconsanguineous parents, have been described among a total of around 30 reported cases.<ref>PMID:19915526</ref> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/PYRD_HUMAN PYRD_HUMAN] Catalyzes the conversion of dihydroorotate to orotate with quinone as electron acceptor. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Human dihydroorotate dehydrogenase (hDHODH) is an attractive target for cancer therapy. Based on its crystal structure, we designed and synthesized a focused compound library containing the structural moiety of 1,4-benzoquinone, which possesses reactive oxygen species (ROS) induction capacity. Compound 3s with a naphtho[2,3-d][1,2,3]triazole-4,9-dione scaffold exhibited inhibitory activity against hDHODH. Further optimization led to compounds 11k and 11l, which inhibited hDHODH activity with IC50 values of 9 and 4.5 nM, respectively. Protein-ligand cocrystal structures clearly depicted hydrogen bond and hydrophobic interactions of 11k and 11l with hDHODH. Compounds 11k and 11l significantly inhibited leukemia cell and solid tumor cell proliferation and induced ROS production, mitochondrial dysfunction, apoptosis, and cell cycle arrest. Nanocrystallization of compound 11l displayed significant in vivo antitumor effects in the Raji xenograft model. Overall, this study provides a novel bifunctional compound 11l with hDHODH inhibition and ROS induction efficacy, which represents a promising anticancer lead worthy of further exploration. | |||
Bifunctional Naphtho[2,3-d][1,2,3]triazole-4,9-dione Compounds Exhibit Antitumor Effects In Vitro and In Vivo by Inhibiting Dihydroorotate Dehydrogenase and Inducing Reactive Oxygen Species Production.,Zuo Z, Liu X, Qian X, Zeng T, Sang N, Liu H, Zhou Y, Tao L, Zhou X, Su N, Yu Y, Chen Q, Luo Y, Zhao Y J Med Chem. 2020 Jul 23;63(14):7633-7652. doi: 10.1021/acs.jmedchem.0c00512. Epub, 2020 Jul 1. PMID:32496056<ref>PMID:32496056</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6lp6" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Dihydroorotate dehydrogenase 3D structures|Dihydroorotate dehydrogenase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Chen Q]] | [[Category: Chen Q]] | ||
[[Category: Yu Y]] | [[Category: Yu Y]] | ||
Latest revision as of 17:41, 29 November 2023
Crystal structure of human DHODH in complex with inhibitor 1214Crystal structure of human DHODH in complex with inhibitor 1214
Structural highlights
DiseasePYRD_HUMAN Defects in DHODH are the cause of postaxial acrofacial dysostosis (POADS) [MIM:263750; also known as Miller syndrome. POADS is characterized by severe micrognathia, cleft lip and/or palate, hypoplasia or aplasia of the posterior elements of the limbs, coloboma of the eyelids and supernumerary nipples. POADS is a very rare disorder: only 2 multiplex families, each consisting of 2 affected siblings born to unaffected, nonconsanguineous parents, have been described among a total of around 30 reported cases.[1] FunctionPYRD_HUMAN Catalyzes the conversion of dihydroorotate to orotate with quinone as electron acceptor. Publication Abstract from PubMedHuman dihydroorotate dehydrogenase (hDHODH) is an attractive target for cancer therapy. Based on its crystal structure, we designed and synthesized a focused compound library containing the structural moiety of 1,4-benzoquinone, which possesses reactive oxygen species (ROS) induction capacity. Compound 3s with a naphtho[2,3-d][1,2,3]triazole-4,9-dione scaffold exhibited inhibitory activity against hDHODH. Further optimization led to compounds 11k and 11l, which inhibited hDHODH activity with IC50 values of 9 and 4.5 nM, respectively. Protein-ligand cocrystal structures clearly depicted hydrogen bond and hydrophobic interactions of 11k and 11l with hDHODH. Compounds 11k and 11l significantly inhibited leukemia cell and solid tumor cell proliferation and induced ROS production, mitochondrial dysfunction, apoptosis, and cell cycle arrest. Nanocrystallization of compound 11l displayed significant in vivo antitumor effects in the Raji xenograft model. Overall, this study provides a novel bifunctional compound 11l with hDHODH inhibition and ROS induction efficacy, which represents a promising anticancer lead worthy of further exploration. Bifunctional Naphtho[2,3-d][1,2,3]triazole-4,9-dione Compounds Exhibit Antitumor Effects In Vitro and In Vivo by Inhibiting Dihydroorotate Dehydrogenase and Inducing Reactive Oxygen Species Production.,Zuo Z, Liu X, Qian X, Zeng T, Sang N, Liu H, Zhou Y, Tao L, Zhou X, Su N, Yu Y, Chen Q, Luo Y, Zhao Y J Med Chem. 2020 Jul 23;63(14):7633-7652. doi: 10.1021/acs.jmedchem.0c00512. Epub, 2020 Jul 1. PMID:32496056[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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