4d6t

Cytochrome bc1 bound to the 4(1H)-pyridone GW844520

spinqualitylabelsall models 4d6t, resolution 3.57Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4d6t is a 19 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 3.57Å Ligands: 4X9, CDL, FES, GOL, HEC, HEM, PEE, PO4 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 Cytochrome bc1 is a proven drug target in the prevention and treatment of malaria. The rise in drug-resistant strains of Plasmodium falciparum, the organism responsible for malaria, has generated a global effort in designing new classes of drugs. Much of the design/redesign work on overcoming this resistance has been focused on compounds that are presumed to bind the Qo site (one of two potential binding sites within cytochrome bc1) using the known crystal structure of this large membrane-bound macromolecular complex via in silico modeling. Cocrystallization of the cytochrome bc1 complex with the 4(1H)-pyridone class of inhibitors, GSK932121 and GW844520, that have been shown to be potent antimalarial agents in vivo, revealed that these inhibitors do not bind at the Qo site but bind at the Qi site. The discovery that these compounds bind at the Qi site may provide a molecular explanation for the cardiotoxicity and eventual failure of GSK932121 in phase-1 clinical trial and highlight the need for direct experimental observation of a compound bound to a target site before chemical optimization and development for clinical trials. The binding of the 4(1H)-pyridone class of inhibitors to Qi also explains the ability of this class to overcome parasite Qo-based atovaquone resistance and provides critical structural information for future design of new selective compounds with improved safety profiles. Antimalarial 4(1H)-pyridones bind to the Qi site of cytochrome bc1.,Capper MJ, O'Neill PM, Fisher N, Strange RW, Moss D, Ward SA, Berry NG, Lawrenson AS, Hasnain SS, Biagini GA, Antonyuk SV Proc Natl Acad Sci U S A. 2015 Jan 6. pii: 201416611. PMID:25564664 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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