4YTM

Crystal structure of Mitochondrial rhodoquinol-fumarate reductase from Ascaris suum with N-biphenyl-3-yl-2-(trifluoromethyl)benzamide

Summary for 4YTM

• Entry DOI: 10.2210/pdb4ytm/pdb
• Related: 4YSX 4YSY 4YSZ 4YT0 4YTN 4YTP 4YXD
• Descriptor: Succinate dehydrogenase flavoprotein, PROTOPORPHYRIN IX CONTAINING FE, N-biphenyl-3-yl-2-(trifluoromethyl)benzamide, ... (12 entities in total)
• Functional Keywords: oxidoreductase, rhodoquinol-fumarate reductase, complex ii, inhibitor, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Ascaris suum (Pig roundworm); More
• Total number of polymer chains: 8
• Total formula weight: 288545.75

Authors

Harada, S.,Shiba, T.,Sato, D.,Yamamoto, A.,Nagahama, M.,Yone, A.,Inaoka, D.K.,Sakamoto, K.,Inoue, M.,Honma, T.,Kita, K. (deposition date: 2015-03-18, release date: 2015-08-05, Last modification date: 2023-11-08)

Primary citation

Inaoka, D.K.,Shiba, T.,Sato, D.,Balogun, E.O.,Sasaki, T.,Nagahama, M.,Oda, M.,Matsuoka, S.,Ohmori, J.,Honma, T.,Inoue, M.,Kita, K.,Harada, S.
Structural Insights into the Molecular Design of Flutolanil Derivatives Targeted for Fumarate Respiration of Parasite Mitochondria
Int J Mol Sci, 16:15287-15308, 2015

PubMed Abstract: Recent studies on the respiratory chain of Ascaris suum showed that the mitochondrial NADH-fumarate reductase system composed of complex I, rhodoquinone and complex II plays an important role in the anaerobic energy metabolism of adult A. suum. The system is the major pathway of energy metabolism for adaptation to a hypoxic environment not only in parasitic organisms, but also in some types of human cancer cells. Thus, enzymes of the pathway are potential targets for chemotherapy. We found that flutolanil is an excellent inhibitor for A. suum complex II (IC50 = 0.058 μM) but less effectively inhibits homologous porcine complex II (IC50 = 45.9 μM). In order to account for the specificity of flutolanil to A. suum complex II from the standpoint of structural biology, we determined the crystal structures of A. suum and porcine complex IIs binding flutolanil and its derivative compounds. The structures clearly demonstrated key interactions responsible for its high specificity to A. suum complex II and enabled us to find analogue compounds, which surpass flutolanil in both potency and specificity to A. suum complex II. Structures of complex IIs binding these compounds will be helpful to accelerate structure-based drug design targeted for complex IIs.

PubMed: 26198225
DOI: 10.3390/ijms160715287

Experimental method

X-RAY DIFFRACTION (3.4 Å)