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- EMDB-71418: CA-SP1 immature lattice assembled in vitro with inhibitor lenacap... -

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Basic information

Entry
Database: EMDB / ID: EMD-71418
TitleCA-SP1 immature lattice assembled in vitro with inhibitor lenacapavir (dialyzed to 50nM)
Map dataphenix anisotropic sharpened map
Sample
  • Virus: Human immunodeficiency virus type 1 (NEW YORK-5 ISOLATE)
    • Protein or peptide: Gag polyprotein
  • Ligand: Lenacapavir
  • Ligand: INOSITOL HEXAKISPHOSPHATE
KeywordsHIV-1 / CA-SP1 / Inhibitor / virion assembly / VIRUS LIKE PARTICLE
Function / homology
Function and homology information


viral budding via host ESCRT complex / host multivesicular body / ISG15 antiviral mechanism / viral nucleocapsid / viral translational frameshifting / host cell nucleus / host cell plasma membrane / virion membrane / structural molecule activity / RNA binding / zinc ion binding
Similarity search - Function
Gag protein p6 / Gag protein p6 / : / gag protein p24 N-terminal domain / Immunodeficiency lentiviral matrix, N-terminal / gag gene protein p17 (matrix protein) / Matrix protein, lentiviral and alpha-retroviral, N-terminal / Retroviral nucleocapsid Gag protein p24, C-terminal domain / Gag protein p24 C-terminal domain / Retrovirus capsid, C-terminal ...Gag protein p6 / Gag protein p6 / : / gag protein p24 N-terminal domain / Immunodeficiency lentiviral matrix, N-terminal / gag gene protein p17 (matrix protein) / Matrix protein, lentiviral and alpha-retroviral, N-terminal / Retroviral nucleocapsid Gag protein p24, C-terminal domain / Gag protein p24 C-terminal domain / Retrovirus capsid, C-terminal / 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.
Similarity search - Domain/homology
Biological speciesHuman immunodeficiency virus type 1 (NEW YORK-5 ISOLATE)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.93 Å
AuthorsWu C / Meuser ME / Xiong Y
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)U54AI170791 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01AI178846 United States
CitationJournal: J Am Chem Soc / Year: 2025
Title: Distinct Target Site of Lenacapavir in Immature HIV-1 and Concurrent Binding with the Maturation Inhibitor Bevirimat.
Authors: Chunxiang Wu / Megan E Meuser / Juan S Rey / Hamed Meshkin / Rachel Yang / Swapnil C Devarkar / Christian Freniere / Jiong Shi / Christopher Aiken / Juan R Perilla / Yong Xiong /
Abstract: HIV-1 inhibitors, such as bevirimat (BVM) and lenacapavir (LEN), significantly reduce the production and maturation of infectious virions. However, their mechanisms remain unclear due to the absence ...HIV-1 inhibitors, such as bevirimat (BVM) and lenacapavir (LEN), significantly reduce the production and maturation of infectious virions. However, their mechanisms remain unclear due to the absence of high-resolution structures for BVM in complex with the immature Gag lattice and LEN's structural data being limited to the mature capsid. Utilizing perforated virus-like particles (VLPs) produced from mammalian cells, we determined in situ cryo-electron microscopy (cryo-EM) structures of HIV-1 with inhibitors. This allowed for the first structural determination of the native immature HIV-1 particle with BVM and LEN bound inside the VLPs at high resolutions. Our findings demonstrate that LEN not only binds the mature capsid but also targets the immature lattice in a distinct manner. The binding of LEN induces a conformational change in the capsid protein (CA) region and alters the architecture of the Gag lattice, which may affect the maturation process. In addition, a more accurate model of BVM engaging the Gag lattice is revealed, one that is independent of LEN binding. These insights expand our understanding of the inhibitory mechanisms of LEN and BVM on HIV-1 and provide valuable clues for the design of future inhibitors.
History
DepositionJun 24, 2025-
Header (metadata) releaseApr 29, 2026-
Map releaseApr 29, 2026-
UpdateApr 29, 2026-
Current statusApr 29, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_71418.png

Downloads & links

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Map

FileDownload / File: emd_71418.map.gz / Format: CCP4 / Size: 166.4 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationphenix anisotropic sharpened map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesX (Sec.)Y (Row.)Z (Col.)
0.86 Å/pix.
x 352 pix.
= 302.72 Å		0.86 Å/pix.
x 352 pix.
= 302.72 Å		0.86 Å/pix.
x 352 pix.
= 302.72 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.86 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0208
Minimum - Maximum-0.14313133 - 0.244133
Average (Standard dev.)0.00004638308 (±0.008848547)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin000
Dimensions352352352
Spacing352352352
CellA=B=C: 302.72 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_71418_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: original map without sharpening

Fileemd_71418_additional_1.map
Annotationoriginal map without sharpening
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: phenix anisotropic sharpened half map

Fileemd_71418_half_map_1.map
Annotationphenix anisotropic sharpened half map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: phenix anisotropic sharpened half map

Fileemd_71418_half_map_2.map
Annotationphenix anisotropic sharpened half map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Human immunodeficiency virus type 1 (NEW YORK-5 ISOLATE)

EntireName: Human immunodeficiency virus type 1 (NEW YORK-5 ISOLATE)
Components
  • Virus: Human immunodeficiency virus type 1 (NEW YORK-5 ISOLATE)
    • Protein or peptide: Gag polyprotein
  • Ligand: Lenacapavir
  • Ligand: INOSITOL HEXAKISPHOSPHATE

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Supramolecule #1: Human immunodeficiency virus type 1 (NEW YORK-5 ISOLATE)

SupramoleculeName: Human immunodeficiency virus type 1 (NEW YORK-5 ISOLATE)
type: virus / ID: 1 / Parent: 0 / Macromolecule list: #1 / Details: recombinantly expressed in E coli / NCBI-ID: 11698
Sci species name: Human immunodeficiency virus type 1 (NEW YORK-5 ISOLATE)
Sci species strain: NL4-3 / Virus type: VIRUS-LIKE PARTICLE / Virus isolate: OTHER / Virus enveloped: No / Virus empty: Yes
Host (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Gag polyprotein

MacromoleculeName: Gag polyprotein / type: protein_or_peptide / ID: 1
Details: recombinant CA-SP1 domain immature lattice in vitro assembled
Number of copies: 18 / Enantiomer: LEVO
Source (natural)Organism: Human immunodeficiency virus type 1 (NEW YORK-5 ISOLATE)
Strain: Clone pNL4-3
Molecular weightTheoretical: 25.339037 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString: VHQAISPRTL NAWVKVVEEK AFSPEVIPMF SALSEGATPQ DLNTMLNTVG GHQAAMQMLK ETINEEAAEW DRLHPVHAGP IAPGQMREP RGSDIAGTTS TLQEQIGWMT HNPPIPVGEI YKRWIILGLN KIVRMYSPTS ILDIRQGPKE PFRDYVDRFY K TLRAEQAS ...String:
VHQAISPRTL NAWVKVVEEK AFSPEVIPMF SALSEGATPQ DLNTMLNTVG GHQAAMQMLK ETINEEAAEW DRLHPVHAGP IAPGQMREP RGSDIAGTTS TLQEQIGWMT HNPPIPVGEI YKRWIILGLN KIVRMYSPTS ILDIRQGPKE PFRDYVDRFY K TLRAEQAS QEVKNWMTET LLVQNANPDC KTILKALGPG ATLEEMMTAC QGVGGPGHKA RVLAEAMSQV T

UniProtKB: Gag polyprotein

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Macromolecule #2: Lenacapavir

MacromoleculeName: Lenacapavir / type: ligand / ID: 2 / Number of copies: 18 / Formula: QNG
Molecular weightTheoretical: 968.282 Da

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Macromolecule #3: INOSITOL HEXAKISPHOSPHATE

MacromoleculeName: INOSITOL HEXAKISPHOSPHATE / type: ligand / ID: 3 / Number of copies: 1 / Formula: IHP
Molecular weightTheoretical: 660.035 Da
Chemical component information

ChemComp-IHP:
INOSITOL HEXAKISPHOSPHATE

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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

Concentration2 mg/mL
BufferpH: 7.4
Component:
ConcentrationFormulaName
50.0 mMTris-HClTris-hydrochloride
1.0 mMIP6Inositol hexaphosphate
50.0 nMLENlenacapavir

Details: the initial Lenacapavir concentration is 180uM and CA-SP1 is 90uM upon particle assembly; the assembled particle is then dialyzed in same buffer, but have final Lenacapavir concentration drop to 50nM.
GridModel: Quantifoil R2/1 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 30 sec. / Details: 15mA
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 283 K / Instrument: FEI VITROBOT MARK IV
Detailsrecombinantly expressed and purified CA-SP1 from E coli. In vitro assembled with excess of Lenacapavir:CA-SP1 ratio (90uM of CA-SP1), and then dialyzed to final Lenacapavir concentration of 50nM.

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Electron microscopy

MicroscopeTFS GLACIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.4 µm / Nominal defocus min: 1.4000000000000001 µm

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Image processing

Particle selectionNumber selected: 3929347
CTF correctionSoftware - Name: cryoSPARC / Software - details: patchCTF / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

9d6c

Final reconstructionApplied symmetry - Point group: C6 (6 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 2.93 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Software - details: local refinement / Number images used: 835109
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC / Software - details: hetergenous refinement
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC / Software - details: local refinement
Final 3D classificationSoftware:
Namedetails
cryoSPARCheterogenous refinement
cryoSPARC3D classification
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

9d6c


Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementProtocol: RIGID BODY FIT
Output model

PDB-9p9m:
CA-SP1 immature lattice assembled in vitro with inhibitor lenacapavir (dialyzed to 50nM)

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