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- PDB-9i8i: cryoEM structure of HIV-1 KAKA/G225R mature CA hexamer -

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Entry
Database: PDB / ID: 9i8i
TitlecryoEM structure of HIV-1 KAKA/G225R mature CA hexamer
ComponentsHIV-1 KAKA/G225R CA hexamer
KeywordsVIRUS / HIV-1 / KAKA/G225R
Biological speciesHIV-1 06TG.HT008 (virus)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.75 Å
AuthorsZhu, Y. / Shen, J. / Shen, Y. / Xu, J. / Zhang, P.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Wellcome Trust United Kingdom
Citation
Journal: Nat Commun / Year: 2025
Title: Structural basis for HIV-1 capsid adaption to a deficiency in IP6 packaging.
Authors: Yanan Zhu / Alex B Kleinpeter / Juan S Rey / Juan Shen / Yao Shen / Jialu Xu / Nathan Hardenbrook / Long Chen / Anka Lucic / Juan R Perilla / Eric O Freed / Peijun Zhang /
Abstract: Inositol hexakisphosphate (IP6) promotes HIV-1 assembly by stabilizing the immature Gag lattice and becomes enriched within virions, where it is required for mature capsid assembly. Previously, we ...Inositol hexakisphosphate (IP6) promotes HIV-1 assembly by stabilizing the immature Gag lattice and becomes enriched within virions, where it is required for mature capsid assembly. Previously, we identified Gag mutants that package little IP6 yet assemble particles, though they are non-infectious due to defective capsid formation. Here, we report a compensatory mutation, G225R, in the C-terminus of capsid protein (CA) that restores capsid assembly and infectivity in these IP6-deficient mutants. G225R also enhances in vitro assembly of CA into capsid-like particles at far lower IP6 concentrations than required for wild-type CA. CryoEM structures of G225R CA hexamers and lattices at 2.7 Å resolution reveal that the otherwise disordered C-terminus becomes structured, stabilizing hexamer-hexamer interfaces. Molecular dynamics simulations support this mechanism. These findings uncover how HIV-1 can adapt to IP6 deficiency and highlight a previously unrecognized structural role of the CA C-terminus, while offering tools for capsid-related studies.
#1: Journal: bioRxiv / Year: 2025
Title: Structural basis for HIV-1 capsid adaption to rescue IP6-packaging deficiency.
Authors: Yanan Zhu / Alex B Kleinpeter / Juan S Rey / Juan Shen / Yao Shen / Jialu Xu / Nathan Hardenbrook / Long Chen / Anka Lucic / Juan R Perilla / Eric O Freed / Peijun Zhang /
Abstract: Inositol hexakisphosphate (IP6) promotes HIV-1 assembly via its interaction with the immature Gag lattice, effectively enriching IP6 within virions. During particle maturation, the HIV-1 protease ...Inositol hexakisphosphate (IP6) promotes HIV-1 assembly via its interaction with the immature Gag lattice, effectively enriching IP6 within virions. During particle maturation, the HIV-1 protease cleaves the Gag polyproteins comprising the immature Gag lattice, releasing IP6 from its original binding site and liberating the capsid (CA) domain of Gag. IP6 then promotes the assembly of mature CA protein into the capsid shell of the viral core, which is required for infection of new target cells. Recently, we reported HIV-1 Gag mutants that assemble virions independently of IP6. However, these mutants are non-infectious and unable to assemble stable capsids. Here, we identified a mutation in the C-terminus of CA - G225R - that restores capsid formation and infectivity to these IP6-packaging-deficient mutants. Furthermore, we show that G225R facilitates the assembly of purified CA into capsid-like particles (CLPs) at IP6 concentrations well below those required for WT CLP assembly. Using single-particle cryoEM, we solved structures of CA hexamer and hexameric lattice of mature CLPs harbouring the G225R mutation assembled in low-IP6 conditions. The high-resolution (2.7 Å) cryoEM structure combined with molecular dynamics simulations of the G225R capsid revealed that the otherwise flexible and disordered C-terminus of CA becomes structured, extending to the pseudo two-fold hexamer-hexamer interface, thereby stabilizing the mature capsid. This work uncovers a structural mechanism by which HIV-1 adapts to a deficiency in IP6 packaging. Furthermore, the ability of G225R to promote mature capsid assembly in low-IP6 conditions provides a valuable tool for capsid-related studies and may indicate a heretofore unknown role for the unstructured C-terminus in HIV-1 capsid assembly.
History
DepositionFeb 5, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 26, 2025Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: HIV-1 KAKA/G225R CA hexamer
F: HIV-1 KAKA/G225R CA hexamer
E: HIV-1 KAKA/G225R CA hexamer
D: HIV-1 KAKA/G225R CA hexamer
C: HIV-1 KAKA/G225R CA hexamer
B: HIV-1 KAKA/G225R CA hexamer


Theoretical massNumber of molelcules
Total (without water)153,6866
Polymers153,6866
Non-polymers00
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
HIV-1 KAKA/G225R CA hexamer


Mass: 25614.365 Da / Num. of mol.: 6
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HIV-1 06TG.HT008 (virus) / Production host: Escherichia coli (E. coli)
Has protein modificationN

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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: HIV-1 KAKA/G225R CA hexamer expressed and isolated from E.coli system
Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: HIV-1 06TG.HT008 (virus)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 6
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: 2000 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 40 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 8443

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Processing

EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C6 (6 fold cyclic)
3D reconstructionResolution: 2.75 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 1646193 / Symmetry type: POINT
RefinementHighest resolution: 2.75 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00310608
ELECTRON MICROSCOPYf_angle_d0.81414424
ELECTRON MICROSCOPYf_dihedral_angle_d5.6631442
ELECTRON MICROSCOPYf_chiral_restr0.0461608
ELECTRON MICROSCOPYf_plane_restr0.0051890

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