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TitleA molecular switch modulates assembly and host factor binding of the HIV-1 capsid.
Journal, issue, pagesNat Struct Mol Biol, Vol. 30, Issue 3, Page 383-390, Year 2023
Publish dateFeb 9, 2023
AuthorsRandall T Schirra / Nayara F B Dos Santos / Kaneil K Zadrozny / Iga Kucharska / Barbie K Ganser-Pornillos / Owen Pornillos /
PubMed AbstractThe 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.
External linksNat Struct Mol Biol / PubMed:36759579 / PubMed Central
MethodsEM (single particle)
Resolution2.2 - 3.9 Å
Structure data

EMDB-26715, PDB-7urn:
Structure of HIV-1 capsid declination
Method: EM (single particle) / Resolution: 3.43 Å

EMDB-26718, PDB-7urt:
T=1 particle HIV-1 CA G60A/G61P/M66A
Method: EM (single particle) / Resolution: 2.39 Å

EMDB-28054, PDB-8eep:
T=1 particle HIV-1 CA G60A/G61P
Method: EM (single particle) / Resolution: 2.2 Å

EMDB-28057, PDB-8eet:
T=1 particle HIV-1 CA M66A
Method: EM (single particle) / Resolution: 3.1 Å

EMDB-28186, PDB-8ejl:
Structure of HIV-1 capsid declination in complex with CPSF6-FG peptide
Method: EM (single particle) / Resolution: 3.9 Å

Chemicals

ChemComp-IHP:
INOSITOL HEXAKISPHOSPHATE / Phytic acid

Source
  • human immunodeficiency virus 1
  • homo sapiens (human)
KeywordsVIRUS LIKE PARTICLE / HIV-1 / capsid / declination / pentamer / hexamer / VIRAL PROTEIN

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