5VQQ

Crystal Structure of HIV-1 Reverse Transcriptase in Complex with N-(6-cyano-3-(2-(2-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)ethoxy)phenoxy)-4-methylnaphthalen-1-yl)-2-fluoro-N-methylacetamide (JLJ683), a Non-nucleoside Inhibitor

5VQQ の概要

• エントリーDOI: 10.2210/pdb5vqq/pdb
• 関連するPDBエントリー: 5TER 5VQR 5VQS 5VQT 5VQU 5VQV 5VQW 5VQX 5VQY 5VQZ
• 分子名称: Reverse transcriptase/ribonuclease H, p51 RT, N-(6-cyano-3-{2-[2-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)ethoxy]phenoxy}-4-methylnaphthalen-1-yl)-2-fluoro-N-methylacetamide, ... (5 entities in total)
• 機能のキーワード: polymerase, reverse transcriptase, non-nucleoside inhibitor, transferase-hydrolase-inhibitor complex, transferase/hydrolase/inhibitor
• 由来する生物種: Human immunodeficiency virus type 1 group M subtype B (isolate BH10) (HIV-1); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 114627.28

構造登録者

Chan, A.H.,Anderson, K.S. (登録日: 2017-05-09, 公開日: 2017-08-23, 最終更新日: 2023-10-04)

主引用文献

Chan, A.H.,Lee, W.G.,Spasov, K.A.,Cisneros, J.A.,Kudalkar, S.N.,Petrova, Z.O.,Buckingham, A.B.,Anderson, K.S.,Jorgensen, W.L.
Covalent inhibitors for eradication of drug-resistant HIV-1 reverse transcriptase: From design to protein crystallography.
Proc. Natl. Acad. Sci. U.S.A., 114:9725-9730, 2017

PubMed Abstract: Development of resistance remains a major challenge for drugs to treat HIV-1 infections, including those targeting the essential viral polymerase, HIV-1 reverse transcriptase (RT). Resistance associated with the Tyr181Cys mutation in HIV-1 RT has been a key roadblock in the discovery of nonnucleoside RT inhibitors (NNRTIs). It is the principal point mutation that arises from treatment of HIV-infected patients with nevirapine, the first-in-class drug still widely used, especially in developing countries. We report covalent inhibitors of Tyr181Cys RT (CRTIs) that can completely knock out activity of the resistant mutant and of the particularly challenging Lys103Asn/Tyr181Cys variant. Conclusive evidence for the covalent modification of Cys181 is provided from enzyme inhibition kinetics, mass spectrometry, protein crystallography, and antiviral activity in infected human T-cell assays. The CRTIs are also shown to be selective for Cys181 and have lower cytotoxicity than the approved NNRTI drugs efavirenz and rilpivirine.

PubMed: 28827354
DOI: 10.1073/pnas.1711463114

実験手法

X-RAY DIFFRACTION (2.55 Å)