EMD-13076
STLV-1 intasome:B56 in complex with the strand-transfer inhibitor raltegravir
EMD-13076
Single-particle3.1 Å
Deposition: 11/06/2021Map released: 18/08/2021
Last modified: 17/07/2024
Sample Organism:
Simian T-lymphotropic virus 1,
Homo sapiens
Sample: Complex of STLV-1 MarB43 integrase with nascent viral DNA, the human PP2A B56 subunit and the inhibitor raltegravir
Fitted models: 7oug (Avg. Q-score: 0.419)
Deposition Authors: Barski MS
,
Ballandras-Colas A
Sample: Complex of STLV-1 MarB43 integrase with nascent viral DNA, the human PP2A B56 subunit and the inhibitor raltegravir
Fitted models: 7oug (Avg. Q-score: 0.419)
Deposition Authors: Barski MS
,
Ballandras-Colas A
Structural basis for the inhibition of HTLV-1 integration inferred from cryo-EM deltaretroviral intasome structures.
Barski MS ,
Vanzo T ,
Zhao XZ ,
Smith SJ ,
Ballandras-Colas A ,
Cronin NB ,
Pye VE ,
Hughes SH ,
Burke Jr TR ,
Cherepanov P ,
Maertens GN
(2021) Nat Commun , 12 , 4996 - 4996
,
Vanzo T ,
Zhao XZ ,
Smith SJ ,
Ballandras-Colas A ,
Cronin NB ,
Pye VE ,
Hughes SH ,
Burke Jr TR ,
Cherepanov P ,
Maertens GN
(2021) Nat Commun , 12 , 4996 - 4996
Abstract:
Between 10 and 20 million people worldwide are infected with the human T-cell lymphotropic virus type 1 (HTLV-1). Despite causing life-threatening pathologies there is no therapeutic regimen for this deltaretrovirus. Here, we screened a library of integrase strand transfer inhibitor (INSTI) candidates built around several chemical scaffolds to determine their effectiveness in limiting HTLV-1 infection. Naphthyridines with substituents in position 6 emerged as the most potent compounds against HTLV-1, with XZ450 having highest efficacy in vitro. Using single-particle cryo-electron microscopy we visualised XZ450 as well as the clinical HIV-1 INSTIs raltegravir and bictegravir bound to the active site of the deltaretroviral intasome. The structures reveal subtle differences in the coordination environment of the Mg2+ ion pair involved in the interaction with the INSTIs. Our results elucidate the binding of INSTIs to the HTLV-1 intasome and support their use for pre-exposure prophylaxis and possibly future treatment of HTLV-1 infection.
Between 10 and 20 million people worldwide are infected with the human T-cell lymphotropic virus type 1 (HTLV-1). Despite causing life-threatening pathologies there is no therapeutic regimen for this deltaretrovirus. Here, we screened a library of integrase strand transfer inhibitor (INSTI) candidates built around several chemical scaffolds to determine their effectiveness in limiting HTLV-1 infection. Naphthyridines with substituents in position 6 emerged as the most potent compounds against HTLV-1, with XZ450 having highest efficacy in vitro. Using single-particle cryo-electron microscopy we visualised XZ450 as well as the clinical HIV-1 INSTIs raltegravir and bictegravir bound to the active site of the deltaretroviral intasome. The structures reveal subtle differences in the coordination environment of the Mg2+ ion pair involved in the interaction with the INSTIs. Our results elucidate the binding of INSTIs to the HTLV-1 intasome and support their use for pre-exposure prophylaxis and possibly future treatment of HTLV-1 infection.