1TV5

Plasmodium falciparum dihydroorotate dehydrogenase with a bound inhibitor

1TV5 の概要

• エントリーDOI: 10.2210/pdb1tv5/pdb
• 分子名称: Dihydroorotate dehydrogenase homolog, mitochondrial, SULFATE ION, (2Z)-2-cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]but-2-enamide, ... (7 entities in total)
• 機能のキーワード: alpha-beta barrel; tim barrel, oxidoreductase
• 由来する生物種: Plasmodium falciparum (malaria parasite P. falciparum)
• 細胞内の位置: Mitochondrion inner membrane (By similarity); Single-pass membrane protein (Potential): Q08210
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 51939.95

構造登録者

Hurt, D.E.,Widom, J.,Clardy, J. (登録日: 2004-06-27, 公開日: 2005-09-06, 最終更新日: 2024-10-09)

主引用文献

Hurt, D.E.,Widom, J.,Clardy, J.
Structure of Plasmodium falciparum dihydroorotate dehydrogenase with a bound inhibitor.
Acta Crystallogr.,Sect.D, 62:312-323, 2006

PubMed Abstract: Membrane-associated dihydroorotate dehydrogenase (DHODH) is an antimalarial therapeutic target without an effective inhibitor. Studies on human DHODH (HsDHODH) led to a structural mechanistic model in which respiratory quinones bind in a tunnel formed by the highly variable N-terminus that leads to the flavin mononucleotide-binding site. The therapeutic agents leflunomide (Arava) and brequinar sodium inhibit HsDHODH by binding in this tunnel. Plasmodium falciparum DHODH (PfDHODH) and HsDHODH have markedly different sensitivities to the two drugs. To understand the structural basis of this differential sensitivity and begin a structure-based drug-design cycle for PfDHODH inhibitors, the three-dimensional structure (2.4 Angstroms, R = 20.1%) of PfDHODH bound to the active metabolite of leflunomide was determined by X-ray crystallography. Comparison of the structures of HsDHODH and PfDHODH reveals a completely different binding mode for the same inhibitor in these two catalytically identical enzymes and explains the previously observed species-specific preferential binding. Because no effective inhibitors have been described for PfDHODH, this structure provides critical insight for the design of potential antimalarials.

PubMed: 16510978
DOI: 10.1107/S0907444905042642

実験手法

X-RAY DIFFRACTION (2.4 Å)