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Open data
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Basic information
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Title | Structure of mitochondrial bc1 in complex with ck-2-68 | |||||||||
![]() | cistemMap Btbc1 ck-2-68 dimer | |||||||||
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![]() | Mitochondrial cytochrome bc1 / antimalarial inhibitor / electron transfer / OXIDOREDUCTASE | |||||||||
Function / homology | ![]() Respiratory electron transport / : / quinol-cytochrome-c reductase / ubiquinol-cytochrome-c reductase activity / mitochondrial electron transport, ubiquinol to cytochrome c / Mitochondrial protein degradation / ubiquinone binding / : / respiratory electron transport chain / mitochondrial membrane ...Respiratory electron transport / : / quinol-cytochrome-c reductase / ubiquinol-cytochrome-c reductase activity / mitochondrial electron transport, ubiquinol to cytochrome c / Mitochondrial protein degradation / ubiquinone binding / : / respiratory electron transport chain / mitochondrial membrane / metalloendopeptidase activity / 2 iron, 2 sulfur cluster binding / oxidoreductase activity / mitochondrial inner membrane / heme binding / mitochondrion / proteolysis / membrane / metal ion binding Similarity search - Function | |||||||||
Biological species | ![]() ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.88 Å | |||||||||
![]() | Xia D / Esser L | |||||||||
Funding support | ![]()
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![]() | ![]() Title: Structure of complex III with bound antimalarial agent CK-2-68 provides insights into selective inhibition of Plasmodium cytochrome bc complexes. Authors: Lothar Esser / Fei Zhou / Allison Zeher / Weimin Wu / Rick Huang / Chang-An Yu / Kristin D Lane / Thomas E Wellems / Di Xia / ![]() 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 ...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 the iron-sulfur protein subunit, which suggests an inhibition mechanism similar to that of P-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 bc, and provide guidance for future development of antimalarials targeting Complex III. | |||||||||
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Structure visualization
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Downloads & links
-EMDB archive
Map data | ![]() | 475.7 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 25.1 KB 25.1 KB | Display Display | ![]() |
Images | ![]() | 131.7 KB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 7tz6MC M: atomic model generated by this map C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Annotation | cistemMap Btbc1 ck-2-68 dimer | ||||||||||||||||||||
Voxel size | X=Y=Z: 0.858 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
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Sample components
+Entire : Bovine heart mitochondrial cytochrome bc1 complex
+Supramolecule #1: Bovine heart mitochondrial cytochrome bc1 complex
+Macromolecule #1: Cytochrome b-c1 complex subunit 1, mitochondrial
+Macromolecule #2: Cytochrome b-c1 complex subunit 2, mitochondrial
+Macromolecule #3: Cytochrome b
+Macromolecule #4: Cytochrome c1, heme protein, mitochondrial
+Macromolecule #5: Cytochrome b-c1 complex subunit Rieske, mitochondrial
+Macromolecule #6: Cytochrome b-c1 complex subunit 7
+Macromolecule #7: Cytochrome b-c1 complex subunit 8
+Macromolecule #8: Cytochrome b-c1 complex subunit 6, mitochondrial
+Macromolecule #9: Cytochrome b-c1 complex subunit Rieske, mitochondrial
+Macromolecule #10: Cytochrome b-c1 complex subunit 9
+Macromolecule #11: Cytochrome b-c1 complex subunit 10
+Macromolecule #12: PROTOPORPHYRIN IX CONTAINING FE
+Macromolecule #13: 7-chloranyl-3-methyl-2-[4-[[4-(trifluoromethyloxy)phenyl]methyl]p...
+Macromolecule #14: HEME C
+Macromolecule #15: FE2/S2 (INORGANIC) CLUSTER
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Concentration | 0.3 mg/mL |
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Buffer | pH: 7.5 / Component - Concentration: 50.0 mM / Component - Name: TrisCl |
Grid | Model: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 400 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 30 sec. |
Vitrification | Cryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Temperature | Min: 80.0 K / Max: 80.0 K |
Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Number grids imaged: 1 / Number real images: 6960 / Average electron dose: 50.24 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Calibrated defocus max: 2.82 µm / Calibrated defocus min: 0.63 µm / Calibrated magnification: 58275 / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.6 µm / Nominal defocus min: 0.7000000000000001 µm / Nominal magnification: 29000 |
Sample stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |