TY  - JOUR
A1  - Kessl, Jacques J.
A1  - Lange, Benjamin B.
A1  - Merbitz-Zahradnik, Torsten
A1  - Zwicker, Klaus
A1  - Hill, Philip
A1  - Meunier, Brigitte
A1  - Pálsdóttir, Hildur
A1  - Hunte, Carola
A1  - Meshnick, Steve
A1  - Trumpower, Bernard L.
T1  - Molecular basis for atovaquone binding to the cytochrome bc1 complex
T2  - Journal of biological chemistry
N2  - Atovaquone is a substituted 2-hydroxynaphthoquinone that is used therapeutically to treat Plasmodium falciparum malaria, Pneumocystis carinii pneumonia, and Toxoplasma gondii toxoplasmosis. It is thought to act on these organisms by inhibiting the cytochrome bc1 complex. We have examined the interaction of atovaquone with the bc1 complex isolated from Saccharomyces cerevisiae, a surrogate, nonpathogenic fungus. Atovaquone inhibits the bc1 complex competitively with apparent Ki = 9 nm, raises the midpoint potential of the Rieske iron-sulfur protein from 285 to 385 mV, and shifts the g values in the EPR spectrum of the Rieske center. These results indicate that atovaquone binds to the ubiquinol oxidation pocket of the bc1 complex, where it interacts with the Rieske iron-sulfur protein. A computed energy-minimized structure for atovaquone liganded to the yeast bc1 complex suggests that a phenylalanine at position 275 of cytochrome b in the bovine bc1 complex, as opposed to leucine at the equivalent position in the yeast enzyme, is responsible for the decreased sensitivity of the bovine bc1 complex (Ki = 80 nm) to atovaquone. When a L275F mutation was introduced into the yeast cytochrome b, the sensitivity of the yeast enzyme to atovaquone decreased (Ki = 100 nm) with no loss in activity, confirming that the L275F exchange contributes to the differential sensitivity of these two species to atovaquone. These results provide the first molecular description of how atovaquone binds to the bc1 complex and explain the differential inhibition of the fungal versus mammalian enzymes.
Y1  - 2021
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/76043
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-760434
SN  - 0021-9258
VL  - 278.2003
IS  - 33
SP  - 31312
EP  - 31318
PB  - American Society for Biochemistry and Molecular Biology Publications
CY  - Bethesda, Md
ER  -