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- PDB-9q50: AK01 integrase inhibitor bound to Wild-type HIV-1 intasome -

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Basic information

Entry
Database: PDB / ID: 9q50
TitleAK01 integrase inhibitor bound to Wild-type HIV-1 intasome
Components
  • DNA (5'-D(*AP*CP*TP*GP*CP*TP*AP*GP*AP*GP*AP*TP*TP*TP*TP*C)-3')
  • DNA (5'-D(P*GP*AP*AP*AP*AP*TP*CP*TP*CP*TP*AP*GP*CP*A)-3')
  • Integrase
KeywordsVIRAL PROTEIN/INHIBITOR/DNA / viral protein / protein complex / integrase inhibitor / VIRAL PROTEIN-INHIBITOR-DNA complex
Function / homology
Function and homology information


HIV-1 retropepsin / symbiont-mediated activation of host apoptosis / retroviral ribonuclease H / exoribonuclease H / exoribonuclease H activity / DNA integration / viral genome integration into host DNA / RNA-directed DNA polymerase / establishment of integrated proviral latency / RNA stem-loop binding ...HIV-1 retropepsin / symbiont-mediated activation of host apoptosis / retroviral ribonuclease H / exoribonuclease H / exoribonuclease H activity / DNA integration / viral genome integration into host DNA / RNA-directed DNA polymerase / establishment of integrated proviral latency / RNA stem-loop binding / viral penetration into host nucleus / host multivesicular body / RNA-directed DNA polymerase activity / RNA-DNA hybrid ribonuclease activity / Transferases; Transferring phosphorus-containing groups; Nucleotidyltransferases / host cell / viral nucleocapsid / DNA recombination / DNA-directed DNA polymerase / aspartic-type endopeptidase activity / Hydrolases; Acting on ester bonds / DNA-directed DNA polymerase activity / symbiont-mediated suppression of host gene expression / viral translational frameshifting / symbiont entry into host cell / lipid binding / host cell nucleus / host cell plasma membrane / virion membrane / structural molecule activity / proteolysis / DNA binding / zinc ion binding / membrane
Similarity search - Function
Reverse transcriptase connection / Reverse transcriptase connection domain / Reverse transcriptase thumb / Reverse transcriptase thumb domain / Integrase Zinc binding domain / Zinc finger integrase-type profile. / Integrase-like, N-terminal / Integrase DNA binding domain / Integrase, C-terminal domain superfamily, retroviral / Integrase, N-terminal zinc-binding domain ...Reverse transcriptase connection / Reverse transcriptase connection domain / Reverse transcriptase thumb / Reverse transcriptase thumb domain / Integrase Zinc binding domain / Zinc finger integrase-type profile. / Integrase-like, N-terminal / Integrase DNA binding domain / Integrase, C-terminal domain superfamily, retroviral / Integrase, N-terminal zinc-binding domain / Integrase, C-terminal, retroviral / Integrase DNA binding domain profile. / Immunodeficiency lentiviral matrix, N-terminal / gag gene protein p17 (matrix protein) / RNase H / Integrase core domain / Integrase, catalytic core / Integrase catalytic domain profile. / Retropepsin-like catalytic domain / Matrix protein, lentiviral and alpha-retroviral, N-terminal / RNase H type-1 domain profile. / Ribonuclease H domain / Retroviral nucleocapsid Gag protein p24, C-terminal domain / Gag protein p24 C-terminal domain / Retropepsins / Retroviral aspartyl protease / Aspartyl protease, retroviral-type family profile. / Peptidase A2A, retrovirus, catalytic / Retrovirus capsid, C-terminal / Reverse transcriptase domain / Reverse transcriptase (RNA-dependent DNA polymerase) / Reverse transcriptase (RT) catalytic domain profile. / Retroviral matrix protein / Retrovirus capsid, N-terminal / zinc finger / Zinc knuckle / Zinc finger, CCHC-type superfamily / Zinc finger, CCHC-type / Zinc finger CCHC-type profile. / Aspartic peptidase, active site / Eukaryotic and viral aspartyl proteases active site. / Aspartic peptidase domain superfamily / Ribonuclease H superfamily / Ribonuclease H-like superfamily / Reverse transcriptase/Diguanylate cyclase domain / DNA/RNA polymerase superfamily
Similarity search - Domain/homology
: / DNA / DNA (> 10) / Gag-Pol polyprotein
Similarity search - Component
Biological speciesHIV-1 06TG.HT008 (virus)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.33 Å
AuthorsJing, T. / Li, M. / Lyumkis, D.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)Z01-BC 006150 and Z01-BC 006198 United States
CitationJournal: NAR Mol Med / Year: 2025
Title: Pi-pi stacking interactions with viral DNA contribute to the potency of naphthyridine-based HIV-1 integrase inhibitors.
Authors: Xue Zhi Zhao / Min Li / Steven J Smith / Arvin Karbasi / Indrani Choudhuri / Tao Jing / Dmitry Lyumkis / Robert Craigie / Terrence R Burke /
Abstract: Drug resistance remains a significant obstacle to identifying effective treatments for HIV-1 infection. Integrase strand transfer inhibitors (INSTIs) are frontline treatments used in combination ...Drug resistance remains a significant obstacle to identifying effective treatments for HIV-1 infection. Integrase strand transfer inhibitors (INSTIs) are frontline treatments used in combination antiretroviral therapy, but their efficacy can be compromised by emergence of resistance-associated mutations. The development of compounds that will retain efficacy against drug-resistant variants is of significant interest. Herein, we report the synthesis of naphthyridine-based INSTIs with a combination of 4-amino and 5-hydroxymethyl groups. Comparison of the resistance mutant profiles of the new compounds with FDA-approved second-generation INSTIs showed that the lead compounds are comparable to or surpass the efficacy of clinically used drugs against some of the most prevalent drug-resistant mutations that emerge in patient-derived viral isolates. High-resolution cryogenic electron microscopy (cryo-EM) structures of HIV-1 intasomes with two of the best naphthyridine-based INSTIs bound highlight how these inhibitors make enhanced interactions with viral DNA, particularly through optimized DNA stacking. Molecular dynamics simulations together with quantum mechanical and molecular mechanical calculations indicate that the interplay between intramolecular bonding, stacking geometry, resonance effects, and charge distribution governs drug binding within the active site of the intasome. The data mechanistically explain how key interactions contribute to improved antiviral potency against drug-resistant mutants and highlight a new strategy to combat HIV-1 resistance.
History
DepositionAug 20, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 14, 2026Provider: repository / Type: Initial release
Revision 1.0Jan 14, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jan 14, 2026Data content type: Additional map / Part number: 1 / Data content type: Additional map / Provider: repository / Type: Initial release
Revision 1.0Jan 14, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Jan 14, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jan 14, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jan 14, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jan 14, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Integrase
C: Integrase
D: Integrase
F: DNA (5'-D(*AP*CP*TP*GP*CP*TP*AP*GP*AP*GP*AP*TP*TP*TP*TP*C)-3')
E: DNA (5'-D(P*GP*AP*AP*AP*AP*TP*CP*TP*CP*TP*AP*GP*CP*A)-3')
B: Integrase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)172,17211
Polymers171,6166
Non-polymers5565
Water1,38777
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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Protein , 1 types, 4 molecules ACDB

#1: Protein
Integrase / IN


Mass: 40149.902 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HIV-1 06TG.HT008 (virus) / Gene: gag-pol
Production host: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
References: UniProt: P12497, Transferases; Transferring phosphorus-containing groups; Nucleotidyltransferases, Hydrolases; Acting on ester bonds

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DNA chain , 2 types, 2 molecules FE

#2: DNA chain DNA (5'-D(*AP*CP*TP*GP*CP*TP*AP*GP*AP*GP*AP*TP*TP*TP*TP*C)-3')


Mass: 5795.758 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) HIV-1 06TG.HT008 (virus)
#3: DNA chain DNA (5'-D(P*GP*AP*AP*AP*AP*TP*CP*TP*CP*TP*AP*GP*CP*A)-3')


Mass: 5220.413 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) HIV-1 06TG.HT008 (virus)

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Non-polymers , 4 types, 82 molecules

#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#6: Chemical ChemComp-A1COF / 4-amino-N-[(2,4-difluorophenyl)methyl]-1-hydroxy-5-(hydroxymethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide


Mass: 376.314 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H14F2N4O4 / Feature type: SUBJECT OF INVESTIGATION
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 77 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: integrase strand transfer inhibitor AK01 bound to HIV-1 wild-type intasome
Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Molecular weightValue: 0.6 MDa / Experimental value: YES
Source (natural)Organism: HIV type 1 (virus)
Source (recombinant)Organism: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
Buffer solutionpH: 6.2
Buffer component
IDConc.NameFormulaBuffer-ID
120 mMTris-HCl1
2600 mMSodium ChlorideNaCl1
35 mMMagnesium ChlorideMgCl21
410 %GlycerolC3H5(OH)31
50.5 mMTCEP1
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationCryogen name: ETHANE
Details: Cryo-EM grids were prepared by freezing using a Vitrobot plunge freezer (Thermo Fisher Scientific) at 20C with 100% humidity

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 105000 X / Nominal defocus max: 2200 nm / Nominal defocus min: 600 nm / Cs: 2.7 mm / C2 aperture diameter: 50 µm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 58 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1RELION5particle selection
2SerialEMimage acquisition
4RELION5CTF correction
7Cootmodel fitting
8UCSF Chimeramodel fitting
10PHENIX1.20.1_4487model refinement
11RELION5initial Euler assignment
12RELION5final Euler assignment
13RELION5classification
14RELION53D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 2.33 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 277019 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL / Target criteria: correlation coefficient
RefinementHighest resolution: 2.33 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0045411
ELECTRON MICROSCOPYf_angle_d0.5727434
ELECTRON MICROSCOPYf_dihedral_angle_d20.306920
ELECTRON MICROSCOPYf_chiral_restr0.045813
ELECTRON MICROSCOPYf_plane_restr0.006833

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