9G9T
Cryo-EM structure of the Toxoplasma gondii respiratory chain complex III inhibited by ELQ-300
This is a non-PDB format compatible entry.
Summary for 9G9T
| Entry DOI | 10.2210/pdb9g9t/pdb |
| EMDB information | 51157 |
| Descriptor | Cytochrome b, Transmembrane protein, CARDIOLIPIN, ... (20 entities in total) |
| Functional Keywords | cytochrome bc1 complex, complex iii, respiratory chain, electron transport |
| Biological source | Toxoplasma gondii More |
| Total number of polymer chains | 24 |
| Total formula weight | 759417.24 |
| Authors | |
| Primary citation | MacLean, A.E.,Shikha, S.,Ferreira Silva, M.,Gramelspacher, M.J.,Nilsen, A.,Liebman, K.M.,Pou, S.,Winter, R.W.,Meir, A.,Riscoe, M.K.,Doggett, J.S.,Sheiner, L.,Muhleip, A. Structure, assembly and inhibition of the Toxoplasma gondii respiratory chain supercomplex. Nat.Struct.Mol.Biol., 2025 Cited by PubMed Abstract: The apicomplexan mitochondrial electron transport chain is essential for parasite survival and displays a divergent subunit composition. Here we report cryo-electron microscopy structures of an apicomplexan III-IV supercomplex and of the drug target complex III. The supercomplex structure reveals how clade-specific subunits form an apicomplexan-conserved III-IV interface with a unique, kinked architecture, suggesting that supercomplexes evolved independently in different eukaryotic lineages. A knockout resulting in supercomplex disassembly challenges the proposed role of III-IV in electron transfer efficiency as suggested for mammals. Nevertheless, knockout analysis indicates that III-IV is critical for parasite fitness. The complexes from the model parasite Toxoplasma gondii were inhibited with the antimalarial atovaquone, revealing interactions underpinning species specificity. They were also inhibited with endochin-like quinolone (ELQ)-300, an inhibitor in late-stage preclinical development. Notably, in the apicomplexan binding site, ELQ-300 is flipped compared with related compounds in the mammalian enzyme. On the basis of the binding modes and parasite-specific interactions discovered, we designed more potent ELQs with subnanomolar activity against T. gondii. Our findings reveal critical evolutionary differences in the role of supercomplexes in mitochondrial biology and provide insight into cytochrome b inhibition, informing future drug discovery. PubMed: 40389671DOI: 10.1038/s41594-025-01531-7 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (1.8 Å) |
Structure validation
Download full validation report
