5k9d
From Proteopedia
Crystal structure of human dihydroorotate dehydrogenase at 1.7 A resolution
Structural highlights
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 PubMedHomeobox transcription factor A9 (HoxA9) is overexpressed in 70% of patients diagnosed with acute myeloid leukemia (AML), whereas only a small subset of AML patients respond to current differentiation therapies. A cell line overexpressing HoxA9 was derived from the bone marrow of a lysozyme-GFP mouse. In this fashion, GFP served as an endogenous reporter of differentiation, permitting a high-throughput phenotypic screen against the MLPCN library. Two chemical scaffolds were optimized for activity yielding compound ML390, and genetic resistance and sequencing efforts identified dihydroorotate dehydrogenase (DHODH) as the target enzyme. The DHODH inhibitor brequinar works against these leukemic cells as well. The X-ray crystal structure of ML390 bound to DHODH elucidates ML390s binding interactions. Development of ML390: A Human DHODH Inhibitor That Induces Differentiation in Acute Myeloid Leukemia.,Lewis TA, Sykes DB, Law JM, Munoz B, Rustiguel JK, Nonato MC, Scadden DT, Schreiber SL ACS Med Chem Lett. 2016 Sep 28;7(12):1112-1117. eCollection 2016 Dec 8. PMID:27994748[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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