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- PDB-8ejl: Structure of HIV-1 capsid declination in complex with CPSF6-FG peptide -

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Basic information

Entry
Database: PDB / ID: 8ejl
TitleStructure of HIV-1 capsid declination in complex with CPSF6-FG peptide
Components
  • Cleavage and polyadenylation specificity factor subunit 6
  • HIV-1 capsid protein
KeywordsVIRAL PROTEIN / HIV-1 / capsid / declination / pentamer / hexamer
Function / homology
Function and homology information


exon-exon junction complex binding / : / positive regulation of RNA export from nucleus / mRNA cleavage factor complex / interchromatin granule / Processing of Intronless Pre-mRNAs / perichromatin fibrils / mRNA cleavage and polyadenylation specificity factor complex / mRNA alternative polyadenylation / paraspeckles ...exon-exon junction complex binding / : / positive regulation of RNA export from nucleus / mRNA cleavage factor complex / interchromatin granule / Processing of Intronless Pre-mRNAs / perichromatin fibrils / mRNA cleavage and polyadenylation specificity factor complex / mRNA alternative polyadenylation / paraspeckles / mRNA 3'-end processing / mRNA 3'-end processing / Signaling by cytosolic FGFR1 fusion mutants / RNA Polymerase II Transcription Termination / protein heterotetramerization / viral budding via host ESCRT complex / ribosomal large subunit binding / Processing of Capped Intron-Containing Pre-mRNA / localization / Signaling by FGFR1 in disease / protein tetramerization / mRNA processing / ISG15 antiviral mechanism / host multivesicular body / viral nucleocapsid / nuclear speck / ribonucleoprotein complex / mRNA binding / host cell nucleus / host cell plasma membrane / virion membrane / structural molecule activity / RNA binding / zinc ion binding / nucleoplasm / membrane / nucleus / cytoplasm
Similarity search - Function
Cleavage and polyadenylation specificity factor subunit 6 / CPSF6/7 family / Gag protein p6 / Gag protein p6 / gag protein p24 N-terminal domain / RNA recognition motif / RNA recognition motif / Eukaryotic RNA Recognition Motif (RRM) profile. / RNA recognition motif domain / RNA-binding domain superfamily ...Cleavage and polyadenylation specificity factor subunit 6 / CPSF6/7 family / Gag protein p6 / Gag protein p6 / gag protein p24 N-terminal domain / RNA recognition motif / RNA recognition motif / Eukaryotic RNA Recognition Motif (RRM) profile. / RNA recognition motif domain / RNA-binding domain superfamily / Immunodeficiency lentiviral matrix, N-terminal / gag gene protein p17 (matrix protein) / Retroviral nucleocapsid Gag protein p24, C-terminal domain / Gag protein p24 C-terminal domain / Matrix protein, lentiviral and alpha-retroviral, N-terminal / 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. / Nucleotide-binding alpha-beta plait domain superfamily
Similarity search - Domain/homology
Gag polyprotein / Cleavage and polyadenylation specificity factor subunit 6
Similarity search - Component
Biological speciesHuman immunodeficiency virus 1
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.9 Å
AuthorsPornillos, O. / Ganser-Pornillos, B.K. / Schirra, R.T. / dos Santos, N.F.B.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI167756 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI150464 United States
CitationJournal: Nat Struct Mol Biol / Year: 2023
Title: A molecular switch modulates assembly and host factor binding of the HIV-1 capsid.
Authors: Randall T Schirra / Nayara F B Dos Santos / Kaneil K Zadrozny / Iga Kucharska / Barbie K Ganser-Pornillos / Owen Pornillos /
Abstract: The HIV-1 capsid is a fullerene cone made of quasi-equivalent hexamers and pentamers of the viral CA protein. Typically, quasi-equivalent assembly of viral capsid subunits is controlled by a ...The HIV-1 capsid is a fullerene cone made of quasi-equivalent hexamers and pentamers of the viral CA protein. Typically, quasi-equivalent assembly of viral capsid subunits is controlled by a molecular switch. Here, we identify a Thr-Val-Gly-Gly motif that modulates CA hexamer/pentamer switching by folding into a 3 helix in the pentamer and random coil in the hexamer. Manipulating the coil/helix configuration of the motif allowed us to control pentamer and hexamer formation in a predictable manner, thus proving its function as a molecular switch. Importantly, the switch also remodels the common binding site for host factors that are critical for viral replication and the new ultra-potent HIV-1 inhibitor lenacapavir. This study reveals that a critical assembly element also modulates the post-assembly and viral replication functions of the HIV-1 capsid and provides new insights on capsid function and inhibition.
History
DepositionSep 17, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 15, 2023Provider: repository / Type: Initial release
Revision 1.1Feb 22, 2023Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 1.2Mar 29, 2023Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Jun 19, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / em_3d_fitting_list
Item: _em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id ..._em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id / _em_3d_fitting_list.source_name / _em_3d_fitting_list.type

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
L: HIV-1 capsid protein
M: HIV-1 capsid protein
N: HIV-1 capsid protein
Y: Cleavage and polyadenylation specificity factor subunit 6
Z: Cleavage and polyadenylation specificity factor subunit 6
A: HIV-1 capsid protein


Theoretical massNumber of molelcules
Total (without water)105,9406
Polymers105,9406
Non-polymers00
Water00
1
L: HIV-1 capsid protein
M: HIV-1 capsid protein
N: HIV-1 capsid protein
Y: Cleavage and polyadenylation specificity factor subunit 6
Z: Cleavage and polyadenylation specificity factor subunit 6
A: HIV-1 capsid protein
x 5


Theoretical massNumber of molelcules
Total (without water)529,69830
Polymers529,69830
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
point symmetry operation4
2


  • Idetical with deposited unit
  • point asymmetric unit
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3


  • Idetical with deposited unit in distinct coordinate
  • point asymmetric unit, std point frame
TypeNameSymmetry operationNumber
transform to point frame1
SymmetryPoint symmetry: (Schoenflies symbol: C5 (5 fold cyclic))

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Components

#1: Protein
HIV-1 capsid protein


Mass: 25630.426 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus 1 / Strain: NL4-3 / Gene: Gag-pol / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P12493
#2: Protein/peptide Cleavage and polyadenylation specificity factor subunit 6 / Cleavage and polyadenylation specificity factor 68 kDa subunit / CPSF 68 kDa subunit / Pre-mRNA ...Cleavage and polyadenylation specificity factor 68 kDa subunit / CPSF 68 kDa subunit / Pre-mRNA cleavage factor Im 68 kDa subunit / Protein HPBRII-4/7


Mass: 1708.952 Da / Num. of mol.: 2 / Fragment: UNP residues 313-327 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: Q16630

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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: Capsid-like particles of in vitro assembled HIV-1 CA protein in complex with CPSF6-FG peptide
Type: COMPLEX
Details: Capsids (0.27 mM CA) were incubated with peptide (3 mM) for 1 hour in ice
Entity ID: all / Source: MULTIPLE SOURCES
Source (natural)Organism: Human immunodeficiency virus 1
Source (recombinant)Organism: Escherichia coli (E. coli) / Strain: BL21(DE3)
Details of virusEmpty: YES / Enveloped: NO / Isolate: OTHER / Type: VIRUS-LIKE PARTICLE
Buffer solutionpH: 6
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: HOMEMADE PLUNGER / Cryogen name: ETHANE / Details: Manual plunge-freezing

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 500 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.20.1_4487: / Classification: refinement
EM software
IDNameVersionCategory
7PHENIXmodel fitting
9cryoSPARCinitial Euler assignment
12cryoSPARCv3.3.13D reconstruction
13PHENIXmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 166463 / Symmetry type: POINT
Atomic model buildingProtocol: OTHER / Space: REAL
Atomic model building

3D fitting-ID: 1 / Source name: PDB / Type: experimental model

IDPDB-IDPdb chain-IDAccession codeInitial refinement model-IDPdb chain residue range
17URN

7urn

A7URN1
27URN

7urn

L7URN1
37URN

7urn

M7URN11-146
47URN

7urn

N7URN1146-221
54WYM

4wym

M4WYM2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0054538
ELECTRON MICROSCOPYf_angle_d0.5146228
ELECTRON MICROSCOPYf_dihedral_angle_d11.631539
ELECTRON MICROSCOPYf_chiral_restr0.039746
ELECTRON MICROSCOPYf_plane_restr0.004796

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