5K9C

Crystal structure of human dihydroorotate dehydrogenase with ML390

5K9C の概要

• エントリーDOI: 10.2210/pdb5k9c/pdb
• 関連するPDBエントリー: 5K9D
• 分子名称: Dihydroorotate dehydrogenase (quinone), mitochondrial, 1-DEOXY-1-(7,8-DIMETHYL-2,4-DIOXO-3,4-DIHYDRO-2H-BENZO[G]PTERIDIN-1-ID-10(5H)-YL)-5-O-PHOSPHONATO-D-RIBITOL, OROTIC ACID, ... (9 entities in total)
• 機能のキーワード: oxidoreductase, alpha/beta barrel, inhibitor, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Mitochondrion inner membrane ; Single-pass membrane protein : Q02127
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 41496.72

構造登録者

Lewis, T.A.,Sykes, D.B.,Law, J.M.,Munoz, B.,Scadden, D.T.,Rustiguel, J.K.,Nonato, M.C.,Schreiber, S.L. (登録日: 2016-05-31, 公開日: 2016-10-12, 最終更新日: 2023-09-27)

主引用文献

Lewis, T.A.,Sykes, D.B.,Law, J.M.,Munoz, B.,Rustiguel, J.K.,Nonato, M.C.,Scadden, D.T.,Schreiber, S.L.
Development of ML390: A Human DHODH Inhibitor That Induces Differentiation in Acute Myeloid Leukemia.
ACS Med Chem Lett, 7:1112-1117, 2016

PubMed Abstract: Homeobox 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.

PubMed: 27994748
DOI: 10.1021/acsmedchemlett.6b00316

実験手法

X-RAY DIFFRACTION (1.66 Å)