5nmi

Cytochrome bc1 bound to the inhibitor MJM170

spinqualitylabelsall models 5nmi, resolution 3.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5nmi is a 22 chain structure with sequence from Bos taurus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 3.5Å Ligands: CDL, FES, HEC, HEM, MJM, PEE Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function QCR1_BOVIN This is a component of the ubiquinol-cytochrome c reductase complex (complex III or cytochrome b-c1 complex), which is part of the mitochondrial respiratory chain. This protein may mediate formation of the complex between cytochromes c and c1. Publication Abstract from PubMed 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 muM) 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. New paradigms for understanding and step changes in treating active and chronic, persistent apicomplexan infections.,McPhillie M, Zhou Y, El Bissati K, Dubey J, Lorenzi H, Capper M, Lukens AK, Hickman M, Muench S, Verma SK, Weber CR, Wheeler K, Gordon J, Sanders J, Moulton H, Wang K, Kim TK, 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 CW, Hasnain SS, Antonyuk SV, Fishwick C, McLeod R Sci Rep. 2016 Jul 14;6:29179. doi: 10.1038/srep29179. PMID:27412848 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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