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- EMDB-47475: Gag CA-SP1 (T8I) immature lattice bound with Bevirimat from envel... -

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Basic information

Entry
Database: EMDB / ID: EMD-47475
TitleGag CA-SP1 (T8I) immature lattice bound with Bevirimat from enveloped virus like particles
Map dataanisotrpic sharpened map by half maps
Sample
  • Virus: Human immunodeficiency virus type 1 (HBX2 ISOLATE)
    • Protein or peptide: Gag
  • Ligand: 3alpha-[(3-carboxy-3-methylbutanoyl)oxy]-8alpha,9beta,10alpha,13alpha,17alpha,19beta-lup-20(29)-en-28-oic acid
  • Ligand: INOSITOL HEXAKISPHOSPHATE
  • Ligand: water
KeywordsHIV-1 / Gag / CA-SP1 / Inhibitor / virion assembly / VIRAL PROTEIN
Function / homology
Function and homology information


Synthesis And Processing Of GAG, GAGPOL Polyproteins / host cellular component / host cell nuclear membrane / Integration of viral DNA into host genomic DNA / Autointegration results in viral DNA circles / Minus-strand DNA synthesis / Plus-strand DNA synthesis / Uncoating of the HIV Virion / 2-LTR circle formation / Vpr-mediated nuclear import of PICs ...Synthesis And Processing Of GAG, GAGPOL Polyproteins / host cellular component / host cell nuclear membrane / Integration of viral DNA into host genomic DNA / Autointegration results in viral DNA circles / Minus-strand DNA synthesis / Plus-strand DNA synthesis / Uncoating of the HIV Virion / 2-LTR circle formation / Vpr-mediated nuclear import of PICs / Early Phase of HIV Life Cycle / viral budding via host ESCRT complex / Integration of provirus / APOBEC3G mediated resistance to HIV-1 infection / Binding and entry of HIV virion / Membrane binding and targetting of GAG proteins / Assembly Of The HIV Virion / Budding and maturation of HIV virion / host multivesicular body / viral nucleocapsid / viral translational frameshifting / 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 (HBX2 ISOLATE)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.71 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)U54 AI170791 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01 AI178846 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
DepositionOct 23, 2024-
Header (metadata) releaseOct 29, 2025-
Map releaseOct 29, 2025-
UpdateApr 29, 2026-
Current statusApr 29, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_47475.png

Downloads & links

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Map

FileDownload / File: emd_47475.map.gz / Format: CCP4 / Size: 286.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationanisotrpic sharpened map by half maps
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesX (Sec.)Y (Row.)Z (Col.)
0.71 Å/pix.
x 422 pix.
= 301.181 Å		0.71 Å/pix.
x 422 pix.
= 301.181 Å		0.71 Å/pix.
x 422 pix.
= 301.181 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.7137 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.018
Minimum - Maximum-0.19390394 - 0.3116609
Average (Standard dev.)0.00039963948 (±0.010838065)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin000
Dimensions422422422
Spacing422422422
CellA=B=C: 301.1814 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_47475_msk_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: raw map without sharpening

Fileemd_47475_additional_1.map
Annotationraw 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: #2

Fileemd_47475_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_47475_half_map_2.map
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Sample components

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Entire : Human immunodeficiency virus type 1 (HBX2 ISOLATE)

EntireName: Human immunodeficiency virus type 1 (HBX2 ISOLATE)
Components
  • Virus: Human immunodeficiency virus type 1 (HBX2 ISOLATE)
    • Protein or peptide: Gag
  • Ligand: 3alpha-[(3-carboxy-3-methylbutanoyl)oxy]-8alpha,9beta,10alpha,13alpha,17alpha,19beta-lup-20(29)-en-28-oic acid
  • Ligand: INOSITOL HEXAKISPHOSPHATE
  • Ligand: water

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Supramolecule #1: Human immunodeficiency virus type 1 (HBX2 ISOLATE)

SupramoleculeName: Human immunodeficiency virus type 1 (HBX2 ISOLATE) / type: virus / ID: 1 / Parent: 0 / Macromolecule list: #1
Details: A codon-optimized Gag plasmid with T8I mutation in the SP1 domain (pCMV-Gag-opt) was expressed in HEK293T cells. The enveloped virion-like particles were purified by filtration and ...Details: A codon-optimized Gag plasmid with T8I mutation in the SP1 domain (pCMV-Gag-opt) was expressed in HEK293T cells. The enveloped virion-like particles were purified by filtration and ultracentrifugation, and directly used as cryo-EM sample.
NCBI-ID: 11706
Sci species name: Human immunodeficiency virus type 1 (HBX2 ISOLATE)
Sci species strain: Clone pNL4-3 / Virus type: VIRUS-LIKE PARTICLE / Virus isolate: STRAIN / Virus enveloped: Yes / Virus empty: Yes
Host (natural)Organism: Homo sapiens (human)
Virus shellShell ID: 1 / Name: Gag

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Macromolecule #1: Gag

MacromoleculeName: Gag / type: protein_or_peptide / ID: 1 / Number of copies: 18 / Enantiomer: LEVO
Source (natural)Organism: Human immunodeficiency virus type 1 (HBX2 ISOLATE)
Strain: isolate HXB2
Molecular weightTheoretical: 25.500176 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: HQAISPRTLN AWVKVVEEKA FSPEVIPMFS ALSEGATPQD LNTMLNTVGG HQAAMQMLKE TINEEAAEWD RVHPVHAGPI APGQMREPR GSDIAGTTST LQEQIGWMTN NPPIPVGEIY KRWIILGLNK IVRMYSPTSI LDIRQGPKEP FRDYVDRFYK T LRAEQASQ ...String:
HQAISPRTLN AWVKVVEEKA FSPEVIPMFS ALSEGATPQD LNTMLNTVGG HQAAMQMLKE TINEEAAEWD RVHPVHAGPI APGQMREPR GSDIAGTTST LQEQIGWMTN NPPIPVGEIY KRWIILGLNK IVRMYSPTSI LDIRQGPKEP FRDYVDRFYK T LRAEQASQ EVKNWMTETL LVQNANPDCK TILKALGPAA TLEEMMTACQ GVGGPGHKAR VLAEAMSQVI NSA

UniProtKB: Gag polyprotein

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Macromolecule #2: 3alpha-[(3-carboxy-3-methylbutanoyl)oxy]-8alpha,9beta,10alpha,13a...

MacromoleculeName: 3alpha-[(3-carboxy-3-methylbutanoyl)oxy]-8alpha,9beta,10alpha,13alpha,17alpha,19beta-lup-20(29)-en-28-oic acid
type: ligand / ID: 2 / Number of copies: 1 / Formula: 2I4
Molecular weightTheoretical: 584.826 Da
Chemical component information

ChemComp-2I4:
3alpha-[(3-carboxy-3-methylbutanoyl)oxy]-8alpha,9beta,10alpha,13alpha,17alpha,19beta-lup-20(29)-en-28-oic acid

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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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Macromolecule #4: water

MacromoleculeName: water / type: ligand / ID: 4 / Number of copies: 7 / 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

Concentration2 mg/mL
BufferpH: 7.4
Component:
ConcentrationNameFormula
10.0 mMTris-hydrocloride
100.0 mMsodium chlorideNaCl
1.0 mMEthylenediaminetetraacetic acid

Details: This is the final buffer in which the enveloped viral like particle was resuspended. The Gag-CA-SP1 lattice is inside the viral like particle and thus not in the direct environment of this buffer.
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 295 K / Instrument: FEI VITROBOT MARK III
DetailsA codon-optimized Gag plasmid with T8I mutation in the SP1 domain (pCMV-Gag-opt) was expressed in HEK293T cells. The enveloped virion like particles were purified by filtration and ultracentrifugation, and directly used as cryo-EM sample.

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 50.0 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: 1.2 µm / Nominal magnification: 81000
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 correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: EMDB MAP
EMDB ID:

45975

Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.71 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 477522
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final 3D classificationNumber classes: 5
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

9cwv


Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementSpace: REAL / Protocol: RIGID BODY FIT
Output model

PDB-9e39:
Gag CA-SP1 (T8I) immature lattice bound with Bevirimat from enveloped virus like particles

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