EMD-27617
Helical reconstruction of A92E HIV capsid in complex with CPSF6 construct (filtered by local resolution)
EMD-27617
Helical reconstruction7.85 Å
Deposition: 13/07/2022Map released: 07/09/2022
Last modified: 17/01/2024
Sample Organism:
Human immunodeficiency virus 1
Sample: HIV Capsid Protein Hexamer
Deposition Authors: Iqbal N
,
Asturias F ,
Kvaratskhelia M
Sample: HIV Capsid Protein Hexamer
Deposition Authors: Iqbal N
,
Asturias F ,
Kvaratskhelia M
Prion-like low complexity regions enable avid virus-host interactions during HIV-1 infection.
Wei G ,
Iqbal N ,
Courouble VV,
Francis AC,
Singh PK ,
Hudait A ,
Annamalai AS,
Bester S ,
Huang SW ,
Shkriabai N,
Briganti L ,
Haney R,
KewalRamani VN ,
Voth GA ,
Engelman AN ,
Melikyan GB,
Griffin PR ,
Asturias F ,
Kvaratskhelia M
(2022) Nat Commun , 13 , 5879 - 5879
,
Iqbal N ,
Courouble VV,
Francis AC,
Singh PK ,
Hudait A ,
Annamalai AS,
Bester S ,
Huang SW ,
Shkriabai N,
Briganti L ,
Haney R,
KewalRamani VN ,
Voth GA ,
Engelman AN ,
Melikyan GB,
Griffin PR ,
Asturias F ,
Kvaratskhelia M
(2022) Nat Commun , 13 , 5879 - 5879
Abstract:
Cellular proteins CPSF6, NUP153 and SEC24C play crucial roles in HIV-1 infection. While weak interactions of short phenylalanine-glycine (FG) containing peptides with isolated capsid hexamers have been characterized, how these cellular factors functionally engage with biologically relevant mature HIV-1 capsid lattices is unknown. Here we show that prion-like low complexity regions (LCRs) enable avid CPSF6, NUP153 and SEC24C binding to capsid lattices. Structural studies revealed that multivalent CPSF6 assembly is mediated by LCR-LCR interactions, which are templated by binding of CPSF6 FG peptides to a subset of hydrophobic capsid pockets positioned along adjoining hexamers. In infected cells, avid CPSF6 LCR-mediated binding to HIV-1 cores is essential for functional virus-host interactions. The investigational drug lenacapavir accesses unoccupied hydrophobic pockets in the complex to potently impair HIV-1 inside the nucleus without displacing the tightly bound cellular cofactor from virus cores. These results establish previously undescribed mechanisms of virus-host interactions and antiviral action.
Cellular proteins CPSF6, NUP153 and SEC24C play crucial roles in HIV-1 infection. While weak interactions of short phenylalanine-glycine (FG) containing peptides with isolated capsid hexamers have been characterized, how these cellular factors functionally engage with biologically relevant mature HIV-1 capsid lattices is unknown. Here we show that prion-like low complexity regions (LCRs) enable avid CPSF6, NUP153 and SEC24C binding to capsid lattices. Structural studies revealed that multivalent CPSF6 assembly is mediated by LCR-LCR interactions, which are templated by binding of CPSF6 FG peptides to a subset of hydrophobic capsid pockets positioned along adjoining hexamers. In infected cells, avid CPSF6 LCR-mediated binding to HIV-1 cores is essential for functional virus-host interactions. The investigational drug lenacapavir accesses unoccupied hydrophobic pockets in the complex to potently impair HIV-1 inside the nucleus without displacing the tightly bound cellular cofactor from virus cores. These results establish previously undescribed mechanisms of virus-host interactions and antiviral action.