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- EMDB-72221: AK01 integrase inhibitor bound to Wild-type HIV-1 intasome -

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Basic information

Entry
Database: EMDB / ID: EMD-72221
TitleAK01 integrase inhibitor bound to Wild-type HIV-1 intasome
Map datamain map
Sample
  • Complex: integrase strand transfer inhibitor AK01 bound to HIV-1 wild-type intasome
    • Protein or peptide: Integrase
    • DNA: DNA (5'-D(*AP*CP*TP*GP*CP*TP*AP*GP*AP*GP*AP*TP*TP*TP*TP*C)-3')
    • DNA: DNA (5'-D(P*GP*AP*AP*AP*AP*TP*CP*TP*CP*TP*AP*GP*CP*A)-3')
  • Ligand: MAGNESIUM ION
  • Ligand: ZINC ION
  • Ligand: 4-amino-N-[(2,4-difluorophenyl)methyl]-1-hydroxy-5-(hydroxymethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide
  • Ligand: water
Keywordsviral 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
Biological speciesHIV type 1 (virus) / HIV-1 06TG.HT008 (virus)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.33 Å
AuthorsJing T / Li M / Lyumkis D
Funding support United States, 1 items
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, 2025-
Header (metadata) releaseJan 14, 2026-
Map releaseJan 14, 2026-
UpdateJan 14, 2026-
Current statusJan 14, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_72221.png

Downloads & links

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Map

FileDownload / File: emd_72221.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationmain map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 360 pix.
= 298.8 Å		0.83 Å/pix.
x 360 pix.
= 298.8 Å		0.83 Å/pix.
x 360 pix.
= 298.8 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.83 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.009
Minimum - Maximum-0.023183966 - 0.057224385
Average (Standard dev.)0.000020108764 (±0.0011114656)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 298.8 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: this is the AR deconvolved map used for accurate water modeling.

Fileemd_72221_additional_1.map
Annotationthis is the AR_deconvolved map used for accurate water modeling.
Projections & Slices
AxesZYX

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Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_72221_half_map_1.map
Projections & Slices
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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_72221_half_map_2.map
Projections & Slices
AxesZYX

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Sample components

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Entire : integrase strand transfer inhibitor AK01 bound to HIV-1 wild-type...

EntireName: integrase strand transfer inhibitor AK01 bound to HIV-1 wild-type intasome
Components
  • Complex: integrase strand transfer inhibitor AK01 bound to HIV-1 wild-type intasome
    • Protein or peptide: Integrase
    • DNA: DNA (5'-D(*AP*CP*TP*GP*CP*TP*AP*GP*AP*GP*AP*TP*TP*TP*TP*C)-3')
    • DNA: DNA (5'-D(P*GP*AP*AP*AP*AP*TP*CP*TP*CP*TP*AP*GP*CP*A)-3')
  • Ligand: MAGNESIUM ION
  • Ligand: ZINC ION
  • Ligand: 4-amino-N-[(2,4-difluorophenyl)methyl]-1-hydroxy-5-(hydroxymethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide
  • Ligand: water

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Supramolecule #1: integrase strand transfer inhibitor AK01 bound to HIV-1 wild-type...

SupramoleculeName: integrase strand transfer inhibitor AK01 bound to HIV-1 wild-type intasome
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: HIV type 1 (virus)
Molecular weightTheoretical: 600 KDa

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Macromolecule #1: Integrase

MacromoleculeName: Integrase / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
EC number: Transferases; Transferring phosphorus-containing groups; Nucleotidyltransferases
Source (natural)Organism: HIV-1 06TG.HT008 (virus)
Molecular weightTheoretical: 40.149902 KDa
Recombinant expressionOrganism: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
SequenceString: MATVKFKYKG EEKEVDISKI KKVWRVGKMI SFTYDEGGGK TGRGAVSEKD APKELLQMLE KQKKGGGGGG GGGGGFLDGI DKAQEEHEK YHSNWRAMAS DFNLPPVVAK EIVASCDKCQ LKGEAMHGQV DCSPGIWQLD CTHLEGKVIL VAVHVASGYI E AEVIPAET ...String:
MATVKFKYKG EEKEVDISKI KKVWRVGKMI SFTYDEGGGK TGRGAVSEKD APKELLQMLE KQKKGGGGGG GGGGGFLDGI DKAQEEHEK YHSNWRAMAS DFNLPPVVAK EIVASCDKCQ LKGEAMHGQV DCSPGIWQLD CTHLEGKVIL VAVHVASGYI E AEVIPAET GQETAYFLLK LAGRWPVKTV HTDNGSNFTS TTVKAACWWA GIKQEFGIPY NPQSQGVIES MNKELKKIIG QV RDQAEHL KTAVQMAVFI HNFKRKGGIG GYSAGERIVD IIATDIQTKE LQKQITKIQN FRVYYRDSRD PVWKGPAKLL WKG EGAVVI QDNSDIKVVP RRKAKIIRDY GKQMAGDDCV ASRQDED

UniProtKB: Gag-Pol polyprotein

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

MacromoleculeName: DNA (5'-D(*AP*CP*TP*GP*CP*TP*AP*GP*AP*GP*AP*TP*TP*TP*TP*C)-3')
type: dna / ID: 2 / Number of copies: 1 / Classification: DNA
Source (natural)Organism: HIV-1 06TG.HT008 (virus)
Molecular weightTheoretical: 5.795758 KDa
SequenceString:
(DA)(DC)(DT)(DG)(DC)(DT)(DA)(DG)(DA)(DG) (DA)(DT)(DT)(DT)(DT)(DC)(DC)(DC)(DG)

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Macromolecule #3: DNA (5'-D(P*GP*AP*AP*AP*AP*TP*CP*TP*CP*TP*AP*GP*CP*A)-3')

MacromoleculeName: DNA (5'-D(P*GP*AP*AP*AP*AP*TP*CP*TP*CP*TP*AP*GP*CP*A)-3')
type: dna / ID: 3 / Number of copies: 1 / Classification: DNA
Source (natural)Organism: HIV-1 06TG.HT008 (virus)
Molecular weightTheoretical: 5.220413 KDa
SequenceString:
(DC)(DG)(DG)(DG)(DA)(DA)(DA)(DA)(DT)(DC) (DT)(DC)(DT)(DA)(DG)(DC)(DA)

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Macromolecule #4: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 4 / Number of copies: 2 / Formula: MG
Molecular weightTheoretical: 24.305 Da

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Macromolecule #5: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 5 / Number of copies: 2 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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Macromolecule #6: 4-amino-N-[(2,4-difluorophenyl)methyl]-1-hydroxy-5-(hydroxymethyl...

MacromoleculeName: 4-amino-N-[(2,4-difluorophenyl)methyl]-1-hydroxy-5-(hydroxymethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide
type: ligand / ID: 6 / Number of copies: 1 / Formula: A1COF
Molecular weightTheoretical: 376.314 Da

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Macromolecule #7: water

MacromoleculeName: water / type: ligand / ID: 7 / Number of copies: 77 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 6.2
Component:
ConcentrationNameFormula
20.0 mMTris-HCl
600.0 mMSodium ChlorideNaCl
5.0 mMMagnesium ChlorideMgCl2
10.0 %GlycerolC3H5(OH)3
0.5 mMTCEP
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Support film - Material: GOLD / Support film - topology: HOLEY
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

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 58.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.2 µm / Nominal defocus min: 0.6 µm / Nominal magnification: 105000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionSoftware - Name: RELION (ver. 5.0) / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER
Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 2.33 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 5.0) / Number images used: 277019
Initial angle assignmentType: PROJECTION MATCHING / Software - Name: RELION (ver. 5.0)
Final angle assignmentType: PROJECTION MATCHING / Software - Name: RELION (ver. 5.0)
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: FLEXIBLE FIT / Target criteria: correlation coefficient
Output model

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

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