7OUH

Structure of the STLV intasome:B56 complex bound to the strand-transfer inhibitor bictegravir

Summary for 7OUH

• Entry DOI: 10.2210/pdb7ouh/pdb
• EMDB information: 13077
• Descriptor: Integrase, PC4 and SFRS1-interacting protein,Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform, DNA (5'-D(*AP*CP*TP*GP*TP*GP*TP*TP*TP*GP*GP*CP*GP*CP*TP*TP*CP*TP*CP*TP*C)-3'), ... (8 entities in total)
• Functional Keywords: integrase, intasome, htlv, stlv, integration, strand-transfer inhibitors, insti, bictegravir, bic, drug, viral protein
• Biological source: Simian T-lymphotropic virus 1; More
• Total number of polymer chains: 10
• Total formula weight: 333452.07

Authors

Barski, M.S.,Ballandras-Colas, A.,Cronin, N.B.,Pye, V.E.,Cherepanov, P.,Maertens, G.N. (deposition date: 2021-06-11, release date: 2021-08-18, Last modification date: 2024-07-17)

Primary citation

Barski, M.S.,Vanzo, T.,Zhao, X.Z.,Smith, S.J.,Ballandras-Colas, A.,Cronin, N.B.,Pye, V.E.,Hughes, S.H.,Burke Jr., T.R.,Cherepanov, P.,Maertens, G.N.
Structural basis for the inhibition of HTLV-1 integration inferred from cryo-EM deltaretroviral intasome structures.
Nat Commun, 12:4996-4996, 2021

PubMed 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 Mg 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.

PubMed: 34404793
DOI: 10.1038/s41467-021-25284-1

Experimental method

ELECTRON MICROSCOPY (3.5 Å)