4OQV

High resolution crystal structure of human dihydroorotate dehydrogenase bound with DSM338 (N-[3,5-difluoro-4-(trifluoromethyl)phenyl]-5-methyl-2-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine)

4OQV の概要

• エントリーDOI: 10.2210/pdb4oqv/pdb
• 関連するPDBエントリー: 4ORI 4ORM
• 分子名称: Dihydroorotate dehydrogenase (quinone), mitochondrial, FLAVIN MONONUCLEOTIDE, OROTIC ACID, ... (9 entities in total)
• 機能のキーワード: alpha/beta barrel, redox, dehydrogenase, fmn, mitochondrial membrane, 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: 42487.79

構造登録者

Deng, X.,Phillips, M.A. (登録日: 2014-02-10, 公開日: 2014-06-04, 最終更新日: 2024-02-28)

主引用文献

Deng, X.,Kokkonda, S.,El Mazouni, F.,White, J.,Burrows, J.N.,Kaminsky, W.,Charman, S.A.,Matthews, D.,Rathod, P.K.,Phillips, M.A.
Fluorine Modulates Species Selectivity in the Triazolopyrimidine Class of Plasmodium falciparum Dihydroorotate Dehydrogenase Inhibitors.
J.Med.Chem., 57:5381-5394, 2014

PubMed Abstract: Malaria is one of the most serious global infectious diseases. The pyrimidine biosynthetic enzyme Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) is an important target for antimalarial chemotherapy. We describe a detailed analysis of protein-ligand interactions between DHODH and a triazolopyrimidine-based inhibitor series to explore the effects of fluorine on affinity and species selectivity. We show that increasing fluorination dramatically increases binding to mammalian DHODHs, leading to a loss of species selectivity. Triazolopyrimidines bind Plasmodium and mammalian DHODHs in overlapping but distinct binding sites. Key hydrogen-bond and stacking interactions underlying strong binding to PfDHODH are absent in the mammalian enzymes. Increasing fluorine substitution leads to an increase in the entropic contribution to binding, suggesting that strong binding to mammalian DHODH is a consequence of an enhanced hydrophobic effect upon binding to an apolar pocket. We conclude that hydrophobic interactions between fluorine and hydrocarbons provide significant binding energy to protein-ligand interactions. Our studies define the requirements for species-selective binding to PfDHODH and show that the triazolopyrimidine scaffold can alternatively be tuned to inhibit human DHODH, an important target for autoimmune diseases.

PubMed: 24801997
DOI: 10.1021/jm500481t

実験手法

X-RAY DIFFRACTION (1.23 Å)