4PD4

Structural analysis of atovaquone-inhibited cytochrome bc1 complex reveals the molecular basis of antimalarial drug action

Summary for 4PD4

• Entry DOI: 10.2210/pdb4pd4/pdb
• Descriptor: Cytochrome b-c1 complex subunit 1, mitochondrial, Igh protein, Ig kappa chain V-V region HP 124E1, ... (18 entities in total)
• Functional Keywords: cytochrome bc1 complex, membrane protein complex, antimalarial drug, inhibitor, oxidoreductase-inhibitor complex, oxidoreductase/inhibitor
• Biological source: Mus musculus (Mouse); More
• Total number of polymer chains: 11
• Total formula weight: 251150.07

Authors

Birth, D.,Kao, W.-C.,Hunte, C. (deposition date: 2014-04-17, release date: 2014-06-11, Last modification date: 2024-11-20)

Primary citation

Birth, D.,Kao, W.C.,Hunte, C.
Structural analysis of atovaquone-inhibited cytochrome bc1 complex reveals the molecular basis of antimalarial drug action.
Nat Commun, 5:4029-4029, 2014

PubMed Abstract: Atovaquone, a substituted hydroxynaphthoquinone, is a potent antimalarial drug that acts by inhibiting the parasite's mitochondrial cytochrome bc1 complex (cyt bc1). Mutations in cyt bc1 confer atovaquone resistance. Here we describe the X-ray structure of mitochondrial cyt bc1 from Saccharomyces cerevisiae with atovaquone bound in the catalytic Qo site, at 3.0-Å resolution. A polarized H-bond to His181 of the Rieske protein in cyt bc1 traps the ionized hydroxyl group of the drug. Side chains of highly conserved cytochrome b residues establish multiple non-polar interactions with the napththoquinone group, whereas less-conserved residues are in contact with atovaquone's cyclohexyl-chlorophenyl tail. Our structural analysis reveals the molecular basis of atovaquone's broad target spectrum, species-specific efficacies and acquired resistances, and may aid drug development to control the spread of resistant parasites.

PubMed: 24893593
DOI: 10.1038/ncomms5029

Experimental method

X-RAY DIFFRACTION (3.04 Å)