9G9T

Cryo-EM structure of the Toxoplasma gondii respiratory chain complex III inhibited by ELQ-300

これはPDB形式変換不可エントリーです。

9G9T の概要

• エントリーDOI: 10.2210/pdb9g9t/pdb
• EMDBエントリー: 51157
• 分子名称: Cytochrome b, Transmembrane protein, CARDIOLIPIN, ... (20 entities in total)
• 機能のキーワード: cytochrome bc1 complex, complex iii, respiratory chain, electron transport
• 由来する生物種: Toxoplasma gondii; 詳細
• タンパク質・核酸の鎖数: 24
• 化学式量合計: 759417.24

構造登録者

MacLean, A.,Muhleip, A. (登録日: 2024-07-25, 公開日: 2025-06-18)

主引用文献

MacLean, A.E.,Shikha, S.,Ferreira Silva, M.,Gramelspacher, M.J.,Nilsen, A.,Liebman, K.M.,Pou, S.,Winter, R.W.,Meir, A.,Riscoe, M.K.,Doggett, J.S.,Sheiner, L.,Muhleip, A.
Structure, assembly and inhibition of the Toxoplasma gondii respiratory chain supercomplex.
Nat.Struct.Mol.Biol., 2025

PubMed Abstract: The apicomplexan mitochondrial electron transport chain is essential for parasite survival and displays a divergent subunit composition. Here we report cryo-electron microscopy structures of an apicomplexan III-IV supercomplex and of the drug target complex III. The supercomplex structure reveals how clade-specific subunits form an apicomplexan-conserved III-IV interface with a unique, kinked architecture, suggesting that supercomplexes evolved independently in different eukaryotic lineages. A knockout resulting in supercomplex disassembly challenges the proposed role of III-IV in electron transfer efficiency as suggested for mammals. Nevertheless, knockout analysis indicates that III-IV is critical for parasite fitness. The complexes from the model parasite Toxoplasma gondii were inhibited with the antimalarial atovaquone, revealing interactions underpinning species specificity. They were also inhibited with endochin-like quinolone (ELQ)-300, an inhibitor in late-stage preclinical development. Notably, in the apicomplexan binding site, ELQ-300 is flipped compared with related compounds in the mammalian enzyme. On the basis of the binding modes and parasite-specific interactions discovered, we designed more potent ELQs with subnanomolar activity against T. gondii. Our findings reveal critical evolutionary differences in the role of supercomplexes in mitochondrial biology and provide insight into cytochrome b inhibition, informing future drug discovery.

PubMed: 40389671
DOI: 10.1038/s41594-025-01531-7

実験手法

ELECTRON MICROSCOPY (1.8 Å)