4D6U

Cytochrome bc1 bound to the 4(1H)-pyridone GSK932121

Summary for 4D6U

• Entry DOI: 10.2210/pdb4d6u/pdb
• Related: 4D6T
• Descriptor: CYTOCHROME B-C1 COMPLEX SUBUNIT 1, MITOCHONDRIAL, CYTOCHROME B-C1 COMPLEX SUBUNIT 2, MITOCHONDRIAL, CYTOCHROME B-C1 COMPLEX SUBUNIT RIESKE, MITOCHONDRIAL, ... (20 entities in total)
• Functional Keywords: oxidoreductase, membrane protein, complex
• Biological source: BOS TAURUS (CATTLE); More
• Total number of polymer chains: 20
• Total formula weight: 573439.65

Authors

Capper, M.J.,ONeill, P.M.,Fisher, N.,Strange, R.W.,Moss, D.,Ward, S.A.,Berry, N.G.,Lawrenson, A.S.,Hasnain, S.S.,Biagini, G.A.,Antonyuk, S.V. (deposition date: 2014-11-14, release date: 2015-01-14, Last modification date: 2025-10-01)

Primary citation

Capper, M.J.,O'Neill, P.M.,Fisher, N.,Strange, R.W.,Moss, D.,Ward, S.A.,Berry, N.G.,Lawrenson, A.S.,Hasnain, S.S.,Biagini, G.A.,Antonyuk, S.V.
Antimalarial 4(1H)-Pyridones Bind to the Qi Site of Cytochrome Bc1.
Proc.Natl.Acad.Sci.USA, 112:755-, 2015

PubMed Abstract: 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 Q(o) 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 Q(o) site but bind at the Q(i )site. The discovery that these compounds bind at the Q(i) 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 Q(i) also explains the ability of this class to overcome parasite Q(o)-based atovaquone resistance and provides critical structural information for future design of new selective compounds with improved safety profiles.

PubMed: 25564664
DOI: 10.1073/PNAS.1416611112

Experimental method

X-RAY DIFFRACTION (4.09 Å)