6VND

Quaternary Complex of human dihydroorotate dehydrogenase (DHODH) with flavin mononucleotide (FMN), orotic acid and AG-636

Summary for 6VND

• Entry DOI: 10.2210/pdb6vnd/pdb
• Descriptor: Dihydroorotate dehydrogenase (quinone), mitochondrial, GLYCEROL, 1-methyl-5-(2'-methyl[1,1'-biphenyl]-4-yl)-1H-benzotriazole-7-carboxylic acid, ... (11 entities in total)
• Functional Keywords: dhodh, oxidoreductase, fmn binding, inhibitor, mitochondria inner membrane, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 42536.97

Authors

Padyana, A.,Jin, L. (deposition date: 2020-01-29, release date: 2020-11-04, Last modification date: 2023-10-11)

Primary citation

McDonald, G.,Chubukov, V.,Coco, J.,Truskowski, K.,Narayanaswamy, R.,Choe, S.,Steadman, M.,Artin, E.,Padyana, A.K.,Jin, L.,Ronseaux, S.,Locuson, C.,Fan, Z.P.,Erdmann, T.,Mann, A.,Hayes, S.,Fletcher, M.,Nellore, K.,Rao, S.S.,Subramanya, H.,Reddy, K.S.,Panigrahi, S.K.,Antony, T.,Gopinath, S.,Sui, Z.,Nagaraja, N.,Dang, L.,Lenz, G.,Hurov, J.,Biller, S.A.,Murtie, J.,Marks, K.M.,Ulanet, D.B.
Selective Vulnerability to Pyrimidine Starvation in Hematologic Malignancies Revealed by AG-636, a Novel Clinical-Stage Inhibitor of Dihydroorotate Dehydrogenase.
Mol.Cancer Ther., 19:2502-2515, 2020

PubMed Abstract: Agents targeting metabolic pathways form the backbone of standard oncology treatments, though a better understanding of differential metabolic dependencies could instruct more rationale-based therapeutic approaches. We performed a chemical biology screen that revealed a strong enrichment in sensitivity to a novel dihydroorotate dehydrogenase (DHODH) inhibitor, AG-636, in cancer cell lines of hematologic versus solid tumor origin. Differential AG-636 activity translated to the setting, with complete tumor regression observed in a lymphoma model. Dissection of the relationship between uridine availability and response to AG-636 revealed a divergent ability of lymphoma and solid tumor cell lines to survive and grow in the setting of depleted extracellular uridine and DHODH inhibition. Metabolic characterization paired with unbiased functional genomic and proteomic screens pointed to adaptive mechanisms to cope with nucleotide stress as contributing to response to AG-636. These findings support targeting of DHODH in lymphoma and other hematologic malignancies and suggest combination strategies aimed at interfering with DNA-damage response pathways.

PubMed: 33082276
DOI: 10.1158/1535-7163.MCT-20-0550

Experimental method

X-RAY DIFFRACTION (1.97 Å)