Structural highlights
9s1i 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.
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| Method: | X-ray diffraction, Resolution 1.61Å |
| 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
Human dihydroorotate dehydrogenase (hDHODH), catalyzing the rate-limiting step of the pyrimidine biosynthesis pathway (PBP), is a drug target extensively investigated for various diseases including cancer, autoimmune disorders, and viral infections. We present evidence that the heterodimeric phloroglucinylpyrone arzanol potently inhibits hDHODH by competing with ubiquinone for binding to the lipophilic patch (LP) of the enzyme. Co-crystallization experiments on the enzyme-arzanol complex provided further insights into the binding pocket of hDHODH, revealing detailed features that could inspire the design of innovative inhibitors. The cellular translation of these enzymatic and biochemical data was validated in antiviral assays on SARS-CoV-2 infected cells. Taken together, these results exemplify the potential of natural products to explore novel areas of the protein druggable space and provide information relevant to multiple critical areas of drug discovery.
Arzanol Inhibits Human Dihydroorotate Dehydrogenase and Shows Antiviral Activity.,Alberti M, Tamburello M, Salamone S, Gallinella G, Sanna C, Appendino GB, Lolli ML, Massarotti A, Pollastro F, Miggiano R J Nat Prod. 2025 Oct 27. doi: 10.1021/acs.jnatprod.5c00887. PMID:41143446[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
- ↑ Alberti M, Tamburello M, Salamone S, Gallinella G, Sanna C, Appendino GB, Lolli ML, Massarotti A, Pollastro F, Miggiano R. Arzanol Inhibits Human Dihydroorotate Dehydrogenase and Shows Antiviral Activity. J Nat Prod. 2025 Oct 27. PMID:41143446 doi:10.1021/acs.jnatprod.5c00887
