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TitleStructural basis for HIV-1 capsid adaption to a deficiency in IP6 packaging.
Journal, issue, pagesNat Commun, Vol. 16, Issue 1, Page 8152, Year 2025
Publish dateSep 1, 2025
AuthorsYanan 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 /
PubMed AbstractInositol 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.
External linksNat Commun / PubMed:40890096 / PubMed Central
MethodsEM (subtomogram averaging) / EM (single particle)
Resolution2.75 - 4.24 Å
Structure data

EMDB-51821: The structure from subtomogram averaging of HIV immature Gag with G225R mutation
Method: EM (subtomogram averaging) / Resolution: 3.79 Å

EMDB-51822: The structure from subtomogram averaging of HIV-1 immature Gag with KAKA/G225R mutations
Method: EM (subtomogram averaging) / Resolution: 4.1 Å

EMDB-51823: The structure from subtomogram averaging of HIV-1 immature Gag with KAKA/T8I/G225R mutations
Method: EM (subtomogram averaging) / Resolution: 4.05 Å

EMDB-51824: The structure from subtomogram averaging of HIV-1 immature Gag with A77V/KAKA/T8I/G225R mutations
Method: EM (subtomogram averaging) / Resolution: 3.78 Å

EMDB-51825: The structure from subtomogram averaging of HIV-1 immature Gag with KAKA/T8I mutations
Method: EM (subtomogram averaging) / Resolution: 3.67 Å

EMDB-51826: The structure from subtomogram averaging of HIV-1 Gag with K227A mutation
Method: EM (subtomogram averaging) / Resolution: 3.82 Å

52724

9i8i

EMDB-52724, PDB-9i8i:
cryoEM structure of HIV-1 KAKA/G225R mature CA hexamer
Method: EM (single particle) / Resolution: 2.75 Å

EMDB-52725: cryoEM structure of HIV-1 KAKA/G225R mature CA tri-hexamer in Class1
Method: EM (single particle) / Resolution: 3.59 Å

EMDB-52726: cryoEM structure of HIV-1 KAKA/G225R mature CA tri-hexamer in Class2
Method: EM (single particle) / Resolution: 4.24 Å

Source
  • hiv-1 06tg.ht008 (virus)
  • uncultured virus (environmental samples)
KeywordsVIRUS / HIV-1 / KAKA/G225R

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