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- PDB-9p9m: CA-SP1 immature lattice assembled in vitro with inhibitor lenacap... -

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Basic information

Entry
Database: PDB / ID: 9p9m
TitleCA-SP1 immature lattice assembled in vitro with inhibitor lenacapavir (dialyzed to 50nM)
ComponentsGag polyprotein
KeywordsVIRUS LIKE PARTICLE / HIV-1 / CA-SP1 / Inhibitor / virion assembly
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
INOSITOL HEXAKISPHOSPHATE / Chem-QNG / Gag polyprotein
Similarity search - Component
Biological speciesHuman immunodeficiency virus type 1
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.93 Å
AuthorsWu, C. / Meuser, M.E. / Xiong, Y.
Funding support United States, 2items
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, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 29, 2026Provider: repository / Type: Initial release
Revision 1.0Apr 29, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Apr 29, 2026Data content type: Additional map / Part number: 1 / Data content type: Additional map / Provider: repository / Type: Initial release
Revision 1.0Apr 29, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Apr 29, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Apr 29, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Apr 29, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Apr 29, 2026Data content type: Mask / Part number: 1 / Data content type: Mask / Provider: repository / Type: Initial release
Revision 1.0Apr 29, 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: Gag polyprotein
B: Gag polyprotein
C: Gag polyprotein
D: Gag polyprotein
E: Gag polyprotein
F: Gag polyprotein
G: Gag polyprotein
H: Gag polyprotein
I: Gag polyprotein
J: Gag polyprotein
K: Gag polyprotein
L: Gag polyprotein
M: Gag polyprotein
N: Gag polyprotein
O: Gag polyprotein
P: Gag polyprotein
Q: Gag polyprotein
R: Gag polyprotein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)474,19237
Polymers456,10318
Non-polymers18,08919
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
Gag polyprotein / Pr55Gag


Mass: 25339.037 Da / Num. of mol.: 18
Fragment: Capsid (CA) domain and Spacer Peptide 1 (SP1) region
Source method: isolated from a genetically manipulated source
Details: recombinant CA-SP1 domain immature lattice in vitro assembled
Source: (gene. exp.) Human immunodeficiency virus type 1 (NEW YORK-5 ISOLATE)
Strain: Clone pNL4-3 / Gene: gag / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P12493
#2: Chemical
ChemComp-QNG / Lenacapavir / Sunlenca / GS-CA1 / GS-6207


Mass: 968.282 Da / Num. of mol.: 18 / Source method: obtained synthetically / Formula: C39H32ClF10N7O5S2 / Feature type: SUBJECT OF INVESTIGATION / Comment: medication, antiretroviral*YM
#3: Chemical ChemComp-IHP / INOSITOL HEXAKISPHOSPHATE / MYO-INOSITOL HEXAKISPHOSPHATE / INOSITOL 1,2,3,4,5,6-HEXAKISPHOSPHATE


Mass: 660.035 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H18O24P6 / 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: Human immunodeficiency virus type 1 (NEW YORK-5 ISOLATE)
Type: VIRUS / Details: recombinantly expressed in E coli / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Human immunodeficiency virus type 1 (NEW YORK-5 ISOLATE)
Strain: NL4-3
Source (recombinant)Organism: Escherichia coli (E. coli) / Strain: BL21(DE3)
Details of virusEmpty: YES / Enveloped: NO / Isolate: OTHER / Type: VIRUS-LIKE PARTICLE
Natural hostOrganism: Homo sapiens
Buffer solutionpH: 7.4
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.
Buffer component
IDConc.NameFormulaBuffer-ID
150 mMTris-hydrochlorideTris-HCl1
21 mMInositol hexaphosphateIP61
350 nMlenacapavirLEN1
SpecimenConc.: 2 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Details: recombinantly 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.
Specimen supportDetails: 15mA / Grid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R2/1
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 283 K

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Electron microscopy imaging

MicroscopyModel: TFS GLACIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2400 nm / Nominal defocus min: 1400 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameVersionCategoryDetails (eV)
1cryoSPARCparticle selectiontemplate picker
2SerialEMimage acquisition
4cryoSPARCCTF correctionpatchCTF
7UCSF ChimeraXmodel fitting
9cryoSPARCinitial Euler assignmenthetergenous refinement
10cryoSPARCfinal Euler assignmentlocal refinement
11cryoSPARCclassificationheterogenous refinement
12cryoSPARCclassification3D classification
13cryoSPARC3D reconstructionlocal refinement
14PHENIX1.21_5207model refinement
15Coot0.98model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 3929347
SymmetryPoint symmetry: C6 (6 fold cyclic)
3D reconstructionResolution: 2.93 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 835109 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT
Atomic model buildingPDB-ID: 9D6C

9d6c


Accession code: 9D6C / Source name: PDB / Type: experimental model
RefinementHighest resolution: 2.93 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00334038
ELECTRON MICROSCOPYf_angle_d0.66746620
ELECTRON MICROSCOPYf_dihedral_angle_d9.3164694
ELECTRON MICROSCOPYf_chiral_restr0.0395022
ELECTRON MICROSCOPYf_plane_restr0.0055910

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