7SLR

HIV Reverse Transcriptase with compound Pyr01

7SLR の概要

• エントリーDOI: 10.2210/pdb7slr/pdb
• 分子名称: Reverse transcriptase/ribonuclease H, 5-(difluoromethyl)-3-({1-[(5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)methyl]-6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl}oxy)-2-methylbenzonitrile (3 entities in total)
• 機能のキーワード: hiv, reverse transcriptase, rt, nnrti, viral protein
• 由来する生物種: Human immunodeficiency virus type 1 (HIV-1)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 129890.63

構造登録者

Klein, D.J.,Zebisch, M.,Gu, M. (登録日: 2021-10-24, 公開日: 2022-11-23, 最終更新日: 2024-05-22)

主引用文献

Balibar, C.J.,Klein, D.J.,Zamlynny, B.,Diamond, T.L.,Fang, Z.,Cheney, C.A.,Kristoff, J.,Lu, M.,Bukhtiyarova, M.,Ou, Y.,Xu, M.,Ba, L.,Carroll, S.S.,El Marrouni, A.,Fay, J.F.,Forster, A.,Goh, S.L.,Gu, M.,Krosky, D.,Rosenbloom, D.I.S.,Sheth, P.,Wang, D.,Wu, G.,Zebisch, M.,Zhao, T.,Zuck, P.,Grobler, J.,Hazuda, D.J.,Howell, B.J.,Converso, A.
Potent targeted activator of cell kill molecules eliminate cells expressing HIV-1.
Sci Transl Med, 15:eabn2038-eabn2038, 2023

PubMed Abstract: Antiretroviral therapy inhibits HIV-1 replication but is not curative due to establishment of a persistent reservoir after virus integration into the host genome. Reservoir reduction is therefore an important HIV-1 cure strategy. Some HIV-1 nonnucleoside reverse transcriptase inhibitors induce HIV-1 selective cytotoxicity in vitro but require concentrations far exceeding approved dosages. Focusing on this secondary activity, we found bifunctional compounds with HIV-1-infected cell kill potency at clinically achievable concentrations. These targeted activator of cell kill (TACK) molecules bind the reverse transcriptase-p66 domain of monomeric Gag-Pol and act as allosteric modulators to accelerate dimerization, resulting in HIV-1 cell death through premature intracellular viral protease activation. TACK molecules retain potent antiviral activity and selectively eliminate infected CD4 T cells isolated from people living with HIV-1, supporting an immune-independent clearance strategy.

PubMed: 36812345
DOI: 10.1126/scitranslmed.abn2038

実験手法

X-RAY DIFFRACTION (2.179 Å)