5NMI

Cytochrome bc1 bound to the inhibitor MJM170

5NMI の概要

• エントリーDOI: 10.2210/pdb5nmi/pdb
• 分子名称: Cytochrome b-c1 complex subunit 1, mitochondrial, ARG-ASN-TRP-VAL-PRO-THR-ALA-GLN-LEU-TRP-GLY-ALA-VAL-GLY-ALA-VAL-GLY-LEU-VAL-SER-ALA-THR, PROTOPORPHYRIN IX CONTAINING FE, ... (16 entities in total)
• 機能のキーワード: membrane protein, inhibitor complex
• 由来する生物種: Bos taurus (Bovine); 詳細
• タンパク質・核酸の鎖数: 22
• 化学式量合計: 549470.81

構造登録者

Capper, N.J.,Antonyuk, S.V.,Hasnain, S.S. (登録日: 2017-04-05, 公開日: 2017-06-14, 最終更新日: 2025-04-09)

主引用文献

McPhillie, M.,Zhou, Y.,El Bissati, K.,Dubey, J.,Lorenzi, H.,Capper, M.,Lukens, A.K.,Hickman, M.,Muench, S.,Verma, S.K.,Weber, C.R.,Wheeler, K.,Gordon, J.,Sanders, J.,Moulton, H.,Wang, K.,Kim, T.K.,He, Y.,Santos, T.,Woods, S.,Lee, P.,Donkin, D.,Kim, E.,Fraczek, L.,Lykins, J.,Esaa, F.,Alibana-Clouser, F.,Dovgin, S.,Weiss, L.,Brasseur, G.,Wirth, D.,Kent, M.,Hood, L.,Meunieur, B.,Roberts, C.W.,Hasnain, S.S.,Antonyuk, S.V.,Fishwick, C.,McLeod, R.
New paradigms for understanding and step changes in treating active and chronic, persistent apicomplexan infections.
Sci Rep, 6:29179-, 2016

PubMed Abstract: Toxoplasma gondii, the most common parasitic infection of human brain and eye, persists across lifetimes, can progressively damage sight, and is currently incurable. New, curative medicines are needed urgently. Herein, we develop novel models to facilitate drug development: EGS strain T. gondii forms cysts in vitro that induce oocysts in cats, the gold standard criterion for cysts. These cysts highly express cytochrome b. Using these models, we envisioned, and then created, novel 4-(1H)-quinolone scaffolds that target the cytochrome bc1 complex Qi site, of which, a substituted 5,6,7,8-tetrahydroquinolin-4-one inhibits active infection (IC50, 30 nM) and cysts (IC50, 4 μM) in vitro, and in vivo (25 mg/kg), and drug resistant Plasmodium falciparum (IC50, <30 nM), with clinically relevant synergy. Mutant yeast and co-crystallographic studies demonstrate binding to the bc1 complex Qi site. Our results have direct impact on improving outcomes for those with toxoplasmosis, malaria, and ~2 billion persons chronically infected with encysted bradyzoites.

PubMed: 27412848
DOI: 10.1038/srep29179

実験手法

X-RAY DIFFRACTION (3.5 Å)