8FN7

Structure of WT HIV-1 intasome bound to Dolutegravir

8FN7 の概要

• エントリーDOI: 10.2210/pdb8fn7/pdb
• EMDBエントリー: 29307
• 分子名称: Lamina-associated polypeptide 2, isoform alpha,Integrase chimera, DNA (27-MER), DNA (25-MER), ... (7 entities in total)
• 機能のキーワード: integrase, nucleoprotein complex, inhibitor, drug resistance, viral protein-dna-inhibitor complex, viral protein/dna/inhibitor
• 由来する生物種: Homo sapiens; 詳細
• タンパク質・核酸の鎖数: 12
• 化学式量合計: 352176.22

構造登録者

Shan, Z.L.,Passos, D.O.,Strutzenberg, T.S.,Li, M.,Lyumkis, D. (登録日: 2022-12-27, 公開日: 2023-08-09, 最終更新日: 2024-11-06)

主引用文献

Li, M.,Oliveira Passos, D.,Shan, Z.,Smith, S.J.,Sun, Q.,Biswas, A.,Choudhuri, I.,Strutzenberg, T.S.,Haldane, A.,Deng, N.,Li, Z.,Zhao, X.Z.,Briganti, L.,Kvaratskhelia, M.,Burke Jr., T.R.,Levy, R.M.,Hughes, S.H.,Craigie, R.,Lyumkis, D.
Mechanisms of HIV-1 integrase resistance to dolutegravir and potent inhibition of drug-resistant variants.
Sci Adv, 9:eadg5953-eadg5953, 2023

PubMed Abstract: HIV-1 infection depends on the integration of viral DNA into host chromatin. Integration is mediated by the viral enzyme integrase and is blocked by integrase strand transfer inhibitors (INSTIs), first-line antiretroviral therapeutics widely used in the clinic. Resistance to even the best INSTIs is a problem, and the mechanisms of resistance are poorly understood. Here, we analyze combinations of the mutations E138K, G140A/S, and Q148H/K/R, which confer resistance to INSTIs. The investigational drug 4d more effectively inhibited the mutants compared with the approved drug Dolutegravir (DTG). We present 11 new cryo-EM structures of drug-resistant HIV-1 intasomes bound to DTG or 4d, with better than 3-Å resolution. These structures, complemented with free energy simulations, virology, and enzymology, explain the mechanisms of DTG resistance involving E138K + G140A/S + Q148H/K/R and show why 4d maintains potency better than DTG. These data establish a foundation for further development of INSTIs that potently inhibit resistant forms in integrase.

PubMed: 37478179
DOI: 10.1126/sciadv.adg5953

実験手法

ELECTRON MICROSCOPY (2.8 Å)