1d3h: Difference between revisions

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New page: left|200px<br /> <applet load="1d3h" size="450" color="white" frame="true" align="right" spinBox="true" caption="1d3h, resolution 1.80Å" /> '''HUMAN DIHYDROOROTAT...
 
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[[Image:1d3h.gif|left|200px]]<br />
<applet load="1d3h" size="450" color="white" frame="true" align="right" spinBox="true"
caption="1d3h, resolution 1.80&Aring;" />
'''HUMAN DIHYDROOROTATE DEHYDROGENASE COMPLEXED WITH ANTIPROLIFERATIVE AGENT A771726'''<br />


==Overview==
==HUMAN DIHYDROOROTATE DEHYDROGENASE COMPLEXED WITH ANTIPROLIFERATIVE AGENT A771726==
BACKGROUND: Dihydroorotate dehydrogenase (DHODH) catalyzes the fourth, committed step in the de novo biosynthesis of pyrimidines. As rapidly, proliferating human T cells have an exceptional requirement for de novo, pyrimidine biosynthesis, small molecule DHODH inhibitors constitute an, attractive therapeutic approach to autoimmune diseases, immunosuppression, and cancer. Neither the structure of human DHODH nor any member of its, family was known. RESULTS: The high-resolution crystal structures of human, DHODH in complex with two different inhibitors have been solved. The, initial set of phases was obtained using multiwavelength anomalous, diffraction phasing with selenomethionine-containing DHODH. The structures, have been refined to crystallographic R factors of 16.8% and 16.2% at, resolutions of 1. 6 A and 1.8 A for inhibitors related to brequinar and, leflunomide, respectively. CONCLUSIONS: Human DHODH has two domains: an, alpha/beta-barrel domain containing the active site and an alpha-helical, domain that forms the opening of a tunnel leading to the active site. Both, inhibitors share a common binding site in this tunnel, and differences in, the binding region govern drug sensitivity or resistance. The active site, of human DHODH is generally similar to that of the previously reported, bacterial active site. The greatest differences are that the catalytic, base removing the proton from dihydroorotate is a serine rather than a, cysteine, and that packing of the flavin mononucleotide in its binding, site is tighter.
<StructureSection load='1d3h' size='340' side='right'caption='[[1d3h]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[1d3h]] 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=1D3H OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1D3H 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]] 1.8&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A26:(2Z)-2-CYANO-3-HYDROXY-N-[4-(TRIFLUOROMETHYL)PHENYL]BUT-2-ENAMIDE'>A26</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=FMN:FLAVIN+MONONUCLEOTIDE'>FMN</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=1d3h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1d3h OCA], [https://pdbe.org/1d3h PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1d3h RCSB], [https://www.ebi.ac.uk/pdbsum/1d3h PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1d3h 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.
== 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/d3/1d3h_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=1d3h ConSurf].
<div style="clear:both"></div>


==About this Structure==
==See Also==
1D3H is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with SO4, ACT, A26, FMN and ORO as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Dihydroorotate_oxidase Dihydroorotate oxidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.3.3.1 1.3.3.1] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1D3H OCA].
*[[Dihydroorotate dehydrogenase 3D structures|Dihydroorotate dehydrogenase 3D structures]]
 
== References ==
==Reference==
<references/>
Structures of human dihydroorotate dehydrogenase in complex with antiproliferative agents., Liu S, Neidhardt EA, Grossman TH, Ocain T, Clardy J, Structure. 2000 Jan 15;8(1):25-33. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=10673429 10673429]
__TOC__
[[Category: Dihydroorotate oxidase]]
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Single protein]]
[[Category: Large Structures]]
[[Category: Clardy, J.]]
[[Category: Clardy J]]
[[Category: Grossman, T.H.]]
[[Category: Grossman TH]]
[[Category: Liu, S.]]
[[Category: Liu S]]
[[Category: Neidhardt, E.A.]]
[[Category: Neidhardt EA]]
[[Category: Ocain, T.]]
[[Category: Ocain T]]
[[Category: A26]]
[[Category: ACT]]
[[Category: FMN]]
[[Category: ORO]]
[[Category: SO4]]
[[Category: alpha-beta barrel]]
[[Category: membrane binding motif]]
[[Category: oxidoreductase]]
 
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 16:28:15 2007''

Latest revision as of 09:48, 7 February 2024

HUMAN DIHYDROOROTATE DEHYDROGENASE COMPLEXED WITH ANTIPROLIFERATIVE AGENT A771726HUMAN DIHYDROOROTATE DEHYDROGENASE COMPLEXED WITH ANTIPROLIFERATIVE AGENT A771726

Structural highlights

1d3h 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 1.8Å
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.

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

See Also

References

  1. ↑ 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

1d3h, resolution 1.80Å

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