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Open data
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Basic information
Entry | Database: PDB / ID: 6rwm | |||||||||
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Title | SIVrcm intasome in complex with bictegravir | |||||||||
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Function / homology | ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() | |||||||||
Biological species | ![]() ![]() | |||||||||
Method | ![]() ![]() ![]() | |||||||||
![]() | Cherepanov, P. / Nans, A. / Cook, N. | |||||||||
Funding support | ![]() ![]()
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![]() | ![]() Title: Structural basis of second-generation HIV integrase inhibitor action and viral resistance. Authors: Nicola J Cook / Wen Li / Dénes Berta / Magd Badaoui / Allison Ballandras-Colas / Andrea Nans / Abhay Kotecha / Edina Rosta / Alan N Engelman / Peter Cherepanov / ![]() ![]() ![]() Abstract: Although second-generation HIV integrase strand-transfer inhibitors (INSTIs) are prescribed throughout the world, the mechanistic basis for the superiority of these drugs is poorly understood. We ...Although second-generation HIV integrase strand-transfer inhibitors (INSTIs) are prescribed throughout the world, the mechanistic basis for the superiority of these drugs is poorly understood. We used single-particle cryo-electron microscopy to visualize the mode of action of the advanced INSTIs dolutegravir and bictegravir at near-atomic resolution. Glutamine-148→histidine (Q148H) and glycine-140→serine (G140S) amino acid substitutions in integrase that result in clinical INSTI failure perturb optimal magnesium ion coordination in the enzyme active site. The expanded chemical scaffolds of second-generation compounds mediate interactions with the protein backbone that are critical for antagonizing viruses containing the Q148H and G140S mutations. Our results reveal that binding to magnesium ions underpins a fundamental weakness of the INSTI pharmacophore that is exploited by the virus to engender resistance and provide a structural framework for the development of this class of anti-HIV/AIDS therapeutics. | |||||||||
Validation Report | ![]() ![]() ![]() | |||||||||
History |
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Structure visualization
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Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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Download
PDBx/mmcif format | ![]() ![]() ![]() |
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PDB format | ![]() ![]() |
PDBML Plus | ![]() |
Others | ![]() |
-Related structure data
Related structure data | ![]() 10042CM ![]() 6rwlC ![]() 6rwnC ![]() 6rwoC C: citing same article ( M: map data used to model this data |
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Similar-shape strucutres |
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Links
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Assembly
Deposited unit | ![]()
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Components
-Protein , 1 types, 12 molecules ABCDFMIJKLNE
#1: Protein | Mass: 32732.182 Da / Num. of mol.: 12 / Mutation: S119D Source method: isolated from a genetically manipulated source Details: SIVrcm integrase, S119D / Source: (gene. exp.) ![]() ![]() ![]() ![]() ![]() |
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-DNA chain , 2 types, 4 molecules TWSQ
#2: DNA chain | Mass: 9223.995 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() #3: DNA chain | Mass: 10134.541 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() |
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-Non-polymers , 5 types, 124 molecules 








#4: Chemical | ChemComp-ZN / ![]() #5: Chemical | ChemComp-MG / ![]() #6: Chemical | ![]() #7: Chemical | ![]() #8: Water | ChemComp-HOH / | ![]() |
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-Experimental details
-Experiment
Experiment | Method: ![]() |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: ![]() |
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Sample preparation
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Molecular weight | Experimental value: NO | ||||||||||||||||||||||||
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Source (recombinant) |
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Buffer solution | pH: 7 | ||||||||||||||||||||||||
Buffer component |
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Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied![]() ![]() | ||||||||||||||||||||||||
Specimen support | Details: no pretreatment / Grid material: ![]() | ||||||||||||||||||||||||
Vitrification![]() | Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 95 % / Chamber temperature: 295 K |
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Electron microscopy imaging
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source![]() ![]() |
Electron lens | Mode: BRIGHT FIELD![]() ![]() |
Specimen holder | Cryogen: NITROGEN / Model: FEI TITAN KRIOS AUTOGRID HOLDER |
Image recording | Electron dose: 55.7 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Num. of grids imaged: 2 / Num. of real images: 11769 |
Image scans | Movie frames/image: 40 / Used frames/image: 1-40 |
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Processing
Software | Name: PHENIX / Version: 1.15.2_3472: / Classification: refinement | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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EM software |
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CTF correction![]() | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Symmetry | Point symmetry![]() ![]() | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
3D reconstruction![]() | Resolution: 2.81 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 149778 / Algorithm: FOURIER SPACE / Details: Non-uniform refinement as implemented in CryoSPARC / Symmetry type: POINT | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Atomic model building | Protocol: RIGID BODY FIT / Space: REAL | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Atomic model building |
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