4igh

From Proteopedia

(Difference between revisions)

Current revision

High resolution crystal structure of human dihydroorotate dehydrogenase bound with 4-quinoline carboxylic acid analog

Structural highlights

4igh is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.3Å
Ligands:	, , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

PYRD_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]

Function

PYRD_HUMAN Catalyzes the conversion of dihydroorotate to orotate with quinone as electron acceptor.

Publication Abstract from PubMed

It is established that drugs targeting viral proteins are at risk of generating resistant strains. However, drugs targeting host factors can potentially avoid this problem. Herein we report structure-activity relationship studies leading to the discovery of a very potent lead compound 6-fluoro-2-(5-isopropyl-2-methyl-4-phenoxyphenyl)quinoline-4-carboxylic acid (C44) that inhibits human dihydroorotate dehydrogenase (DHODH) with an IC50 of 1 nM, and viral replication of VSV and WSN-Influenza with an EC50 of 2 nM and 41 nM. We also solved the X-ray structure of human DHODH bound to C44, providing structural insight into the potent inhibition of biaryl ether analogs of brequinar.

SAR Based Optimization of a 4-Quinoline Carboxylic Acid Analog with Potent Anti-Viral Activity.,Das P, Deng X, Zhang L, Roth MG, Fontoura BM, Phillips MA, De Brabander JK ACS Med Chem Lett. 2013 Jun 13;4(6):517-521. PMID:23930152^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Ng SB, Buckingham KJ, Lee C, Bigham AW, Tabor HK, Dent KM, Huff CD, Shannon PT, Jabs EW, Nickerson DA, Shendure J, Bamshad MJ. Exome sequencing identifies the cause of a mendelian disorder. Nat Genet. 2010 Jan;42(1):30-5. doi: 10.1038/ng.499. Epub 2009 Nov 13. PMID:19915526 doi:10.1038/ng.499
↑ Das P, Deng X, Zhang L, Roth MG, Fontoura BM, Phillips MA, De Brabander JK. SAR Based Optimization of a 4-Quinoline Carboxylic Acid Analog with Potent Anti-Viral Activity. ACS Med Chem Lett. 2013 Jun 13;4(6):517-521. PMID:23930152 doi:10.1021/ml300464h

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4igh"

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 4igh is ON HOLD
+==High resolution crystal structure of human dihydroorotate dehydrogenase bound with 4-quinoline carboxylic acid analog==
+<StructureSection load='4igh' size='340' side='right'caption='[[4igh]], [[Resolution|resolution]] 1.30&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[4igh]] 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=4IGH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4IGH 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]] 1.3&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1EA:6-FLUORO-2-[2-METHYL-4-PHENOXY-5-(PROPAN-2-YL)PHENYL]QUINOLINE-4-CARBOXYLIC+ACID'>1EA</scene>, <scene name='pdbligand=FMN:FLAVIN+MONONUCLEOTIDE'>FMN</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=ORO:OROTIC+ACID'>ORO</scene>, <scene name='pdbligand=ZWI:3-[DECYL(DIMETHYL)AMMONIO]PROPANE-1-SULFONATE'>ZWI</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=4igh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4igh OCA], [https://pdbe.org/4igh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4igh RCSB], [https://www.ebi.ac.uk/pdbsum/4igh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4igh ProSAT]</span></td></tr>
+</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 ==
+It is established that drugs targeting viral proteins are at risk of generating resistant strains. However, drugs targeting host factors can potentially avoid this problem. Herein we report structure-activity relationship studies leading to the discovery of a very potent lead compound 6-fluoro-2-(5-isopropyl-2-methyl-4-phenoxyphenyl)quinoline-4-carboxylic acid (C44) that inhibits human dihydroorotate dehydrogenase (DHODH) with an IC50 of 1 nM, and viral replication of VSV and WSN-Influenza with an EC50 of 2 nM and 41 nM. We also solved the X-ray structure of human DHODH bound to C44, providing structural insight into the potent inhibition of biaryl ether analogs of brequinar.
-Authors: Deng, X., Das, P., Fontoura, B.M.A., Phillips, M.A., De Brabander, J.K.
+SAR Based Optimization of a 4-Quinoline Carboxylic Acid Analog with Potent Anti-Viral Activity.,Das P, Deng X, Zhang L, Roth MG, Fontoura BM, Phillips MA, De Brabander JK ACS Med Chem Lett. 2013 Jun 13;4(6):517-521. PMID:23930152<ref>PMID:23930152</ref>
-Description: High resolution crystal structure of human dihydroorotate dehydrogenase bound with 4-quinoline carboxylic acid analog
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 4igh" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Dihydroorotate dehydrogenase 3D structures|Dihydroorotate dehydrogenase 3D structures]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Das P]]
+[[Category: De Brabander JK]]
+[[Category: Deng X]]
+[[Category: Fontoura BMA]]
+[[Category: Phillips MA]]

4igh

From Proteopedia

Current revision

High resolution crystal structure of human dihydroorotate dehydrogenase bound with 4-quinoline carboxylic acid analog

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox