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- PDB-6xvf: Crystal structure of bovine cytochrome bc1 in complex with tetrah... -
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Open data
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Basic information
Entry | Database: PDB / ID: 6xvf | |||||||||
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Title | Crystal structure of bovine cytochrome bc1 in complex with tetrahydro-quinolone inhibitor JAG021 | |||||||||
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![]() | MEMBRANE PROTEIN / Cytochrome bc1 / Malaria / Electron transport | |||||||||
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 / mitochondrial inner membrane / oxidoreductase activity / heme binding / mitochondrion / proteolysis / membrane / metal ion binding Similarity search - Function | |||||||||
Biological species | ![]() ![]() | |||||||||
Method | ![]() ![]() ![]() | |||||||||
![]() | Amporndanai, K. / Hasnain, S.S. / Antonyuk, S.V. | |||||||||
![]() | ![]() Title: Potent Tetrahydroquinolone Eliminates Apicomplexan Parasites. Authors: Martin J McPhillie / Ying Zhou / Mark R Hickman / James A Gordon / Christopher R Weber / Qigui Li / Patty J Lee / Kangsa Amporndanai / Rachel M Johnson / Heather Darby / Stuart Woods / Zhu- ...Authors: Martin J McPhillie / Ying Zhou / Mark R Hickman / James A Gordon / Christopher R Weber / Qigui Li / Patty J Lee / Kangsa Amporndanai / Rachel M Johnson / Heather Darby / Stuart Woods / Zhu-Hong Li / Richard S Priestley / Kurt D Ristroph / Scott B Biering / Kamal El Bissati / Seungmin Hwang / Farida Esaa Hakim / Sarah M Dovgin / Joseph D Lykins / Lucy Roberts / Kerrie Hargrave / Hua Cong / Anthony P Sinai / Stephen P Muench / Jitender P Dubey / Robert K Prud'homme / Hernan A Lorenzi / Giancarlo A Biagini / Silvia N Moreno / Craig W Roberts / Svetlana V Antonyuk / Colin W G Fishwick / Rima McLeod / ![]() ![]() Abstract: Apicomplexan infections cause substantial morbidity and mortality, worldwide. New, improved therapies are needed. Herein, we create a next generation anti-apicomplexan lead compound, JAG21, a ...Apicomplexan infections cause substantial morbidity and mortality, worldwide. New, improved therapies are needed. Herein, we create a next generation anti-apicomplexan lead compound, JAG21, a tetrahydroquinolone, with increased sp3-character to improve parasite selectivity. Relative to other cytochrome inhibitors, JAG21 has improved solubility and ADMET properties, without need for pro-drug. JAG21 significantly reduces tachyzoites and encysted bradyzoites , and in primary and established chronic murine infections. Moreover, JAG21 treatment leads to 100% survival. Further, JAG21 is efficacious against drug-resistant . Causal prophylaxis and radical cure are achieved after sporozoite infection with oral administration of a single dose (2.5 mg/kg) or 3 days treatment at reduced dose (0.625 mg/kg/day), eliminating parasitemia, and leading to 100% survival. Enzymatic, binding, and co-crystallography/pharmacophore studies demonstrate selectivity for apicomplexan relative to mammalian enzymes. JAG21 has significant promise as a pre-clinical candidate for prevention, treatment, and cure of toxoplasmosis and malaria. | |||||||||
History |
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Structure visualization
Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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Download
PDBx/mmCIF format | ![]() | 842.7 KB | Display | ![]() |
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PDB format | ![]() | 688.4 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Arichive directory | ![]() ![]() | HTTPS FTP |
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-Related structure data
Related structure data | ![]() 5okdS S: Starting model for refinement C: citing same article ( |
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Similar structure data |
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Links
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Assembly
Deposited unit | ![]()
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1 | ![]()
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Unit cell |
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Components
-Cytochrome b-c1 complex subunit ... , 8 types, 8 molecules ABEFGHIJ
#1: Protein | Mass: 49165.152 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
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#2: Protein | Mass: 44495.000 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
#5: Protein | Mass: 21640.580 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
#6: Protein | Mass: 12485.247 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
#7: Protein | Mass: 8799.227 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
#8: Protein | Mass: 7515.433 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
#9: Protein/peptide | Mass: 4827.567 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
#10: Protein | Mass: 6866.897 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
-Protein , 2 types, 2 molecules CD
#3: Protein | Mass: 42489.145 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
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#4: Protein | Mass: 27107.021 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
-Sugars , 1 types, 1 molecules ![](data/chem/img/LMT.gif)
#16: Sugar | ChemComp-LMT / |
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-Non-polymers , 11 types, 44 molecules ![](data/chem/img/PG4.gif)
![](data/chem/img/6PE.gif)
![](data/chem/img/PO4.gif)
![](data/chem/img/CDL.gif)
![](data/chem/img/HEM.gif)
![](data/chem/img/PEE.gif)
![](data/chem/img/JAG.gif)
![](data/chem/img/HEC.gif)
![](data/chem/img/FES.gif)
![](data/chem/img/PX4.gif)
![](data/chem/img/HOH.gif)
![](data/chem/img/6PE.gif)
![](data/chem/img/PO4.gif)
![](data/chem/img/CDL.gif)
![](data/chem/img/HEM.gif)
![](data/chem/img/PEE.gif)
![](data/chem/img/JAG.gif)
![](data/chem/img/HEC.gif)
![](data/chem/img/FES.gif)
![](data/chem/img/PX4.gif)
![](data/chem/img/HOH.gif)
#11: Chemical | #12: Chemical | ChemComp-6PE / | #13: Chemical | ChemComp-PO4 / #14: Chemical | ChemComp-CDL / #15: Chemical | #17: Chemical | #18: Chemical | ChemComp-JAG / | #19: Chemical | ChemComp-HEC / | #20: Chemical | ChemComp-FES / | #21: Chemical | ChemComp-PX4 / | #22: Water | ChemComp-HOH / | |
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-Details
Has ligand of interest | Y |
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-Experimental details
-Experiment
Experiment | Method: ![]() |
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Sample preparation
Crystal | Density Matthews: 4.86 Å3/Da / Density % sol: 74.7 % / Description: Bipyramidal red crystals |
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Crystal grow | Temperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.8 Details: Protein 40mg/mL with 1.6% HECAMEG; Reservoir solution: 50mM KPi pH 6.8, 100mM NaCl, 3mM NaN3, 10-13% PEG4000 |
-Data collection
Diffraction | Mean temperature: 100 K / Serial crystal experiment: N |
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Diffraction source | Source: ![]() ![]() ![]() |
Detector | Type: DECTRIS EIGER2 X 9M / Detector: PIXEL / Date: Dec 1, 2017 / Details: mirrors |
Radiation | Monochromator: Si111 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 0.9801 Å / Relative weight: 1 |
Reflection | Resolution: 3.45→90.88 Å / Num. obs: 53526 / % possible obs: 91.4 % / Redundancy: 11.4 % / Biso Wilson estimate: 94.4 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.225 / Rpim(I) all: 0.068 / Rrim(I) all: 0.235 / Net I/σ(I): 8.6 |
Reflection shell | Resolution: 3.45→3.56 Å / Redundancy: 11.6 % / Rmerge(I) obs: 1.111 / Mean I/σ(I) obs: 2.4 / Num. unique obs: 4659 / CC1/2: 0.295 / Rpim(I) all: 0.334 / % possible all: 92.8 |
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Processing
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Refinement | Method to determine structure: ![]() Starting model: 5OKD Resolution: 3.5→90.88 Å / Cor.coef. Fo:Fc: 0.874 / Cor.coef. Fo:Fc free: 0.911 / SU B: 0.584 / SU ML: 0.374 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.493 / Details: U VALUES : WITH TLS ADDED
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Solvent computation | Ion probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso max: 304.39 Å2 / Biso mean: 165.129 Å2 / Biso min: 28.77 Å2
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Refinement step | Cycle: final / Resolution: 3.5→90.88 Å
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Refine LS restraints |
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LS refinement shell | Resolution: 3.5→3.591 Å / Rfactor Rfree error: 0
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Refinement TLS params. | Method: refined / Refine-ID: X-RAY DIFFRACTION
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Refinement TLS group |
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