7TZ6

Structure of mitochondrial bc1 in complex with ck-2-68

7TZ6 の概要

• エントリーDOI: 10.2210/pdb7tz6/pdb
• EMDBエントリー: 26203
• 分子名称: Cytochrome b-c1 complex subunit 1, mitochondrial, Cytochrome b-c1 complex subunit 9, Cytochrome b-c1 complex subunit 10, ... (15 entities in total)
• 機能のキーワード: mitochondrial cytochrome bc1, antimalarial inhibitor, electron transfer, oxidoreductase
• 由来する生物種: Bos taurus (cattle); 詳細
• タンパク質・核酸の鎖数: 22
• 化学式量合計: 487471.01

構造登録者

Xia, D.,Esser, L.,Zhou, F.,Huang, R. (登録日: 2022-02-15, 公開日: 2023-02-22, 最終更新日: 2024-11-06)

主引用文献

Esser, L.,Zhou, F.,Zeher, A.,Wu, W.,Huang, R.,Yu, C.A.,Lane, K.D.,Wellems, T.E.,Xia, D.
Structure of complex III with bound antimalarial agent CK-2-68 provides insights into selective inhibition of Plasmodium cytochrome bc 1 complexes.
J.Biol.Chem., 299:104860-104860, 2023

PubMed Abstract: Among the various components of the protozoan Plasmodium mitochondrial respiratory chain, only Complex III is a validated cellular target for antimalarial drugs. The compound CK-2-68 was developed to specifically target the alternate NADH dehydrogenase of the malaria parasite respiratory chain, but the true target for its antimalarial activity has been controversial. Here, we report the cryo-EM structure of mammalian mitochondrial Complex III bound with CK-2-68 and examine the structure-function relationships of the inhibitor's selective action on Plasmodium. We show that CK-2-68 binds specifically to the quinol oxidation site of Complex III, arresting the motion of the iron-sulfur protein subunit, which suggests an inhibition mechanism similar to that of P-type Complex III inhibitors such as atovaquone, stigmatellin, and UHDBT. Our results shed light on the mechanisms of observed resistance conferred by mutations, elucidate the molecular basis of the wide therapeutic window of CK-2-68 for selective action of Plasmodium vs. host cytochrome bc, and provide guidance for future development of antimalarials targeting Complex III.

PubMed: 37236355
DOI: 10.1016/j.jbc.2023.104860

実験手法

ELECTRON MICROSCOPY (2.88 Å)