Structure of Complex III with Bound Antimalarial Agent CK-2-68 Provides Insights into Selective Inhibition of Plasmodium Cytochrome bc1 Complexes

Author:

Esser, Lothar

Zhou, Fei

Zeher, Allison

Wu, Weimin

Huang, Rick

Yu, Chang-An

Lane, Kristin D

Wellems, Thomas E

Xia, Di
Author Address

Laboratory of Cell Biology, Center for Cancer Research National Cancer Institute, NIH, Bethesda, MD, USA., Laboratory of Cell Biology, Center for Cancer Research National Cancer Institute, NIH, Bethesda, MD, USA; NIH Intramural Cryo-EM Consortium (NICE), Bethesda, MD, USA., Center for Molecular Microscopy, Center for Cancer Research, National Cancer Institute, NIH, Frederick, MD, USA., Department of Biochemistry, Oklahoma State University, Stillwater, OK, USA., Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA., Laboratory of Cell Biology, Center for Cancer Research National Cancer Institute, NIH, Bethesda, MD, USA. Electronic address: xiad@mail.nih.gov.,

Abstract:

Among the various components of the protozoan Plasmodium mitochondrial respiratory chain, only Complex III is a validated cellular target for antimalarial drugs. The compound CK-2-68 was developed to specifically target the alternate NADH dehydrogenase of the malaria parasite respiratory chain, but the true target for its antimalarial activity has been controversial. Here, we report the cryo-EM structure of mammalian mitochondrial Complex III bound with CK-2-68 and examine the structure-function relationships of the inhibitor's selective action on Plasmodium. We show that CK-2-68 binds specifically to the quinol oxidation site of Complex III, arresting the motion of iron-sulfur protein subunit, which suggests an inhibition mechanism similar to that of Pf-type Complex III inhibitors such as atovaquone, stigmatellin, and UHDBT. Our results shed light on the mechanisms of observed resistance conferred by mutations, elucidate the molecular basis of the wide therapeutic window of CK-2-68 for selective action of Plasmodium vs. host cytochrome bc1, and provide guidance for future development of antimalarials targeting Complex III. Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

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