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- PDB-26nl: Cryo-EM Structure of the HIV Capsid in Complex with VHL-3 -

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Basic information

Entry
Database: PDB / ID: 26nl
TitleCryo-EM Structure of the HIV Capsid in Complex with VHL-3
Components
  • 2LZ-WFP-A1E9U-BAL-TBG-HYP
  • Capsid protein p24
KeywordsVIRAL PROTEIN / HIV / Capsid / Inhibitor
Function / homology
Function and homology information


retroviral ribonuclease H / exoribonuclease H / symbiont-mediated activation of host apoptosis / HIV-1 retropepsin / exoribonuclease H activity / DNA integration / viral genome integration into host DNA / establishment of integrated proviral latency / host multivesicular body / RNA-directed DNA polymerase ...retroviral ribonuclease H / exoribonuclease H / symbiont-mediated activation of host apoptosis / HIV-1 retropepsin / exoribonuclease H activity / DNA integration / viral genome integration into host DNA / establishment of integrated proviral latency / host multivesicular body / RNA-directed DNA polymerase / viral penetration into host nucleus / 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 / lipid binding / symbiont entry into host cell / host cell nucleus / host cell plasma membrane / virion membrane / structural molecule activity / proteolysis / DNA binding / RNA binding / zinc ion binding
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 DNA binding domain / Integrase, C-terminal domain superfamily, retroviral / Integrase, N-terminal zinc-binding domain / Integrase, C-terminal, retroviral ...Reverse transcriptase connection / Reverse transcriptase connection domain / Reverse transcriptase thumb / Reverse transcriptase thumb domain / Integrase Zinc binding domain / Zinc finger integrase-type profile. / Integrase DNA binding domain / Integrase, C-terminal domain superfamily, retroviral / Integrase, N-terminal zinc-binding domain / Integrase, C-terminal, retroviral / Integrase-like, N-terminal / 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 / Reverse transcriptase (RNA-dependent DNA polymerase) / Retrovirus capsid, C-terminal / Retroviral matrix protein / Reverse transcriptase domain / Reverse transcriptase (RT) catalytic domain profile. / 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
: / polypeptide(D) / Gag-Pol polyprotein
Similarity search - Component
Biological speciesHuman immunodeficiency virus 1
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.8 Å
AuthorsXue, L. / Gui, J.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32400116 China
CitationJournal: J Med Chem / Year: 2026
Title: Targeted Degradation of Capsid by Host-Hijacking PROTAC Overcomes Drug Resistance.
Authors: Mei Wang / Zeyu Peng / Yang Zhou / Yuexi Ma / Jiacheng Gui / Shujing Xu / Xiangyi Jiang / Tianyu Tang / Xinyong Liu / Christophe Pannecouque / Lu Xue / Xiaoli Xiong / Kai Tang / Guochao Wei / Peng Zhan /
Abstract: The escalating prevalence of HIV-1 drug-resistant variants and the toxicity limitations of conventional antiretroviral therapies necessitate therapeutic strategies with novel mechanisms of action. ...The escalating prevalence of HIV-1 drug-resistant variants and the toxicity limitations of conventional antiretroviral therapies necessitate therapeutic strategies with novel mechanisms of action. This study focuses on HIV-1 capsid (CA), an essential replication-related viral protein. We developed CA-targeted proteolysis-targeting chimera (PROTAC) degraders by conjugating PF74-derived CA ligand with VHL E3 ligase ligand. Among these, - exhibited potent anti-HIV-1 activity in MT-4 cells (EC = 3.0 ± 1.5 nM), a 300-fold improvement over PF74. Mechanistic studies confirmed VHL-3 dose- and time-dependently reduced CA levels in HEK293T cells (early stage, DC = 812 nM; late stage, DC = 252 nM) via a proteasome-driven pathway. Notably, it effectively degraded clinically relevant CA-resistant mutants (N74D, K70R). This work pioneers the development of CA-targeted degraders, providing a framework for next-generation anti-HIV therapies with high potency and resistance barriers.
History
DepositionMay 7, 2026Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Jul 22, 2026Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Capsid protein p24
B: Capsid protein p24
C: Capsid protein p24
D: Capsid protein p24
E: Capsid protein p24
F: Capsid protein p24
G: 2LZ-WFP-A1E9U-BAL-TBG-HYP
H: 2LZ-WFP-A1E9U-BAL-TBG-HYP
I: 2LZ-WFP-A1E9U-BAL-TBG-HYP
J: 2LZ-WFP-A1E9U-BAL-TBG-HYP
K: 2LZ-WFP-A1E9U-BAL-TBG-HYP
L: 2LZ-WFP-A1E9U-BAL-TBG-HYP
hetero molecules


Theoretical massNumber of molelcules
Total (without water)158,98118
Polymers157,67112
Non-polymers1,3106
Water00
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

#1: Protein
Capsid protein p24 / CA


Mass: 25437.229 Da / Num. of mol.: 6
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus 1 / Gene: gag-pol / Production host: Escherichia coli (E. coli) / References: UniProt: P0C6F2
#2: Polypeptide(D)
2LZ-WFP-A1E9U-BAL-TBG-HYP


Mass: 841.272 Da / Num. of mol.: 6 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#3: Chemical
ChemComp-A1E9V / (1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethanamine


Mass: 218.318 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C12H14N2S / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationY

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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: Cryo-EM Structure of the HIV Capsid in Complex with VHL-3
Type: COMPLEX / Entity ID: #1 / Source: MULTIPLE SOURCES
Source (natural)Organism: Human immunodeficiency virus 1
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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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 defocus max: 2400 nm / Nominal defocus min: 600 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: TFS FALCON 4i (4k x 4k)

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Processing

EM software
IDNameCategory
1cryoSPARCparticle selection
2PHENIXmodel refinement
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 3293231 / Symmetry type: POINT
RefinementHighest resolution: 2.8 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00310538
ELECTRON MICROSCOPYf_angle_d0.75514367
ELECTRON MICROSCOPYf_dihedral_angle_d9.281560
ELECTRON MICROSCOPYf_chiral_restr0.0431597
ELECTRON MICROSCOPYf_plane_restr0.0061872

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