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- PDB-8fnn: Structure of E138K/G140A/Q148K HIV-1 intasome with Dolutegravir bound -
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Open data
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Basic information
Entry | Database: PDB / ID: 8fnn | ||||||||||||||||||
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Title | Structure of E138K/G140A/Q148K HIV-1 intasome with Dolutegravir bound | ||||||||||||||||||
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Function / homology | ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() Similarity search - Function | ||||||||||||||||||
Biological species | ![]() ![]() ![]() ![]() ![]() | ||||||||||||||||||
Method | ![]() ![]() ![]() | ||||||||||||||||||
![]() | Shan, Z.L. / Passos, D.O. / Strutzenberg, T.S. / Li, M. / Lyumkis, D. | ||||||||||||||||||
Funding support | ![]()
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![]() | ![]() Title: Mechanisms of HIV-1 integrase resistance to dolutegravir and potent inhibition of drug-resistant variants. Authors: Min Li / Dario Oliveira Passos / Zelin Shan / Steven J Smith / Qinfang Sun / Avik Biswas / Indrani Choudhuri / Timothy S Strutzenberg / Allan Haldane / Nanjie Deng / Zhaoyang Li / Xue Zhi ...Authors: Min Li / Dario Oliveira Passos / Zelin Shan / Steven J Smith / Qinfang Sun / Avik Biswas / Indrani Choudhuri / Timothy S Strutzenberg / Allan Haldane / Nanjie Deng / Zhaoyang Li / Xue Zhi Zhao / Lorenzo Briganti / Mamuka Kvaratskhelia / Terrence R Burke / Ronald M Levy / Stephen H Hughes / Robert Craigie / Dmitry Lyumkis / ![]() Abstract: HIV-1 infection depends on the integration of viral DNA into host chromatin. Integration is mediated by the viral enzyme integrase and is blocked by integrase strand transfer inhibitors (INSTIs), ...HIV-1 infection depends on the integration of viral DNA into host chromatin. Integration is mediated by the viral enzyme integrase and is blocked by integrase strand transfer inhibitors (INSTIs), first-line antiretroviral therapeutics widely used in the clinic. Resistance to even the best INSTIs is a problem, and the mechanisms of resistance are poorly understood. Here, we analyze combinations of the mutations E138K, G140A/S, and Q148H/K/R, which confer resistance to INSTIs. The investigational drug 4d more effectively inhibited the mutants compared with the approved drug Dolutegravir (DTG). We present 11 new cryo-EM structures of drug-resistant HIV-1 intasomes bound to DTG or 4d, with better than 3-Å resolution. These structures, complemented with free energy simulations, virology, and enzymology, explain the mechanisms of DTG resistance involving E138K + G140A/S + Q148H/K/R and show why 4d maintains potency better than DTG. These data establish a foundation for further development of INSTIs that potently inhibit resistant forms in integrase. | ||||||||||||||||||
History |
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Structure visualization
Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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Download
PDBx/mmCIF format | ![]() | 321.8 KB | Display | ![]() |
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PDB format | ![]() | 247.7 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Arichive directory | ![]() ![]() | HTTPS FTP |
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-Related structure data
Related structure data | ![]() 29319MC ![]() 8fn7C ![]() 8fndC ![]() 8fngC ![]() 8fnhC ![]() 8fnjC ![]() 8fnlC ![]() 8fnmC ![]() 8fnoC ![]() 8fnpC ![]() 8fnqC C: citing same article ( M: map data used to model this data |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
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Assembly
Deposited unit | ![]()
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Components
-Protein , 1 types, 8 molecules ABCDGHIJ
#1: Protein | Mass: 39913.500 Da / Num. of mol.: 8 / Mutation: E138K,G140A,Q148K Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() ![]() ![]() Gene: TMPO, LAP2, gag-pol / Production host: ![]() ![]() ![]() References: UniProt: P42166, UniProt: P12497, ![]() ![]() |
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-DNA chain , 2 types, 4 molecules EKFL
#2: DNA chain | Mass: 8188.271 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) ![]() ![]() ![]() #3: DNA chain | Mass: 7773.023 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) ![]() ![]() ![]() |
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-Non-polymers , 4 types, 601 molecules ![](data/chem/img/MG.gif)
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![](data/chem/img/DLU.gif)
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![](data/chem/img/DLU.gif)
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#4: Chemical | ChemComp-MG / #5: Chemical | #6: Chemical | ![]() #7: 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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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: ![]() |
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Sample preparation
Component | Name: E138K/G140A/Q148K HIV-1 intasome bound to dolutegravir Type: COMPLEX / Entity ID: #1-#3 / Source: MULTIPLE SOURCES | |||||||||||||||||||||||||||||||||||||||||||||
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Molecular weight | Value: 0.5 MDa / Experimental value: NO | |||||||||||||||||||||||||||||||||||||||||||||
Source (natural) |
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Source (recombinant) | Organism: ![]() ![]() ![]() | |||||||||||||||||||||||||||||||||||||||||||||
Buffer solution | pH: 7.5 | |||||||||||||||||||||||||||||||||||||||||||||
Buffer component |
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Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied![]() ![]() | |||||||||||||||||||||||||||||||||||||||||||||
Specimen support | Grid material: GOLD / Grid type: Quantifoil | |||||||||||||||||||||||||||||||||||||||||||||
Vitrification![]() | Cryogen name: ETHANE |
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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 / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER |
Image recording | Electron dose: 30 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) |
EM imaging optics | Energyfilter name![]() |
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Processing
EM software |
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CTF correction![]() | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||
Particle selection | Num. of particles selected: 677866 | ||||||||||||||||
Symmetry | Point symmetry![]() ![]() | ||||||||||||||||
3D reconstruction![]() | Resolution: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 99619 / Symmetry type: POINT | ||||||||||||||||
Atomic model building | Protocol: FLEXIBLE FIT / Space: REAL |