5K9C
Crystal structure of human dihydroorotate dehydrogenase with ML390
Summary for 5K9C
| Entry DOI | 10.2210/pdb5k9c/pdb |
| Related | 5K9D |
| Descriptor | 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) |
| Functional Keywords | oxidoreductase, alpha/beta barrel, inhibitor, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor |
| Biological source | Homo sapiens (Human) |
| Cellular location | Mitochondrion inner membrane ; Single-pass membrane protein : Q02127 |
| Total number of polymer chains | 1 |
| Total formula weight | 41496.72 |
| Authors | Lewis, T.A.,Sykes, D.B.,Law, J.M.,Munoz, B.,Scadden, D.T.,Rustiguel, J.K.,Nonato, M.C.,Schreiber, S.L. (deposition date: 2016-05-31, release date: 2016-10-12, Last modification date: 2023-09-27) |
| Primary citation | 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 Cited by 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: 27994748DOI: 10.1021/acsmedchemlett.6b00316 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.66 Å) |
Structure validation
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