Extended Data Fig. 8: Structural divergence of the apicomplexan cytochrome-b and the different mode of inhibition of the parasite and host by atovaquone.
From: Structure, assembly and inhibition of the Toxoplasma gondii respiratory chain supercomplex
(a) T. gondii supercomplex structure with heme molecules and inhibitors (ELQ-300 and atovaquone (ATQ)) (b) Cryo-EM map (left) and model (right) of the C. sabaeus CIII. (c) Schematic of the C. sabaeus CIII with heme groups and two ATQ copies (orange) per monomer shown. Inset depicts close-up view of the Qi site occupied with atovaquone. (d) Overlay of Cyt-b structures from T. gondii, C. sabaeus (both this study) and S. cerevisiae with the module of helices F-H highlighted. (e) Comparison of helices F,G,H. The T. gondii helices F and H are straight and lack the conserved proline residues (red) found in the opisthokont homologs. (f) Overlay of the atovaquone-inhibited Cyt-b structures from T. gondii and C. sabaeus showing that the kink in the mammalian helix F causes it to extend further into the Qo site. Two affected residues interacting with ATQ are shown. (g) Multiple sequence alignment showing the absence of conserved proline residues (red) in helices F and H. Tg, Toxoplasma gondii; Pf, Plasmodium falciparum; Pm, Plasmodium malariae, Pk, Plasmodium knowlesi; Pv, Plasmodium vivax; Po, Plasmodium ovale; Hs, Homo sapiens; Cs, Chlorocebus sabaeus; Sc, Saccharomyces cerevisiae. (h) T. gondii Qo site with ATQ and surrounding conserved residues (map in blue). (i) Comparison of atovaquone bound Qo sites in T. gondii (left) and S. cerevisiae (right; PDB 4pd4). (j) Ligand diagram of atovaquone in the C. sabaeus Qi site.
