7AIF

HIV-1 REVERSE TRANSCRIPTASE COMPLEX WITH DNA AND L-GLUTAMATE TENOFOVIR WITH BOUND MANGANESE

7AIF の概要

• エントリーDOI: 10.2210/pdb7aif/pdb
• 分子名称: Gag-Pol polyprotein, DNA (5'-D(P*GP*GP*TP*CP*GP*GP*CP*GP*CP*CP*CP*GP*AP*AP*CP*AP*GP*GP*GP*AP*CP*TP*G)-3'), DNA (5'-D(*CP*AP*GP*TP*CP*CP*CP*TP*GP*TP*TP*CP*GP*GP*(MRG)P*CP*GP*CP*CP*(DDG))-3'), ... (7 entities in total)
• 機能のキーワード: reverse transcriptase, rt inhibitor complex, tenofovir analog, rt-dna complex, transferase
• 由来する生物種: Human immunodeficiency virus type 1 BH10; 詳細
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 258891.51

構造登録者

Gu, W.,Martinez, S.E.,Nguyen, H.,Xu, H.,Herdewijn, P.,de Jonghe, S.,Das, K. (登録日: 2020-09-27, 公開日: 2021-01-13, 最終更新日: 2024-01-31)

主引用文献

Gu, W.,Martinez, S.,Nguyen, H.,Xu, H.,Herdewijn, P.,De Jonghe, S.,Das, K.
Tenofovir-Amino Acid Conjugates Act as Polymerase Substrates-Implications for Avoiding Cellular Phosphorylation in the Discovery of Nucleotide Analogues.
J.Med.Chem., 64:782-796, 2021

PubMed Abstract: Nucleotide analogues are used for treating viral infections such as HIV, hepatitis B, hepatitis C, influenza, and SARS-CoV-2. To become polymerase substrates, a nucleotide analogue must be phosphorylated by cellular kinases which is rate-limiting. The goal of this study is to develop dNTP/NTP analogues directly from nucleotides. Tenofovir (TFV) analogues were synthesized by conjugating with amino acids. We demonstrate that some conjugates act as dNTP analogues and HIV-1 reverse transcriptase (RT) catalytically incorporates the TFV part as the chain terminator. X-ray structures in complex with HIV-1 RT/dsDNA showed binding of the conjugates at the polymerase active site, however, in different modes in the presence of Mg versus Mn ions. The adaptability of the compounds is seemingly essential for catalytic incorporation of TFV by RT. with a carboxyl sidechain demonstrated the highest incorporation. showed weak incorporation and rather behaved as a dNTP-competitive inhibitor. This result advocates the feasibility of designing NTP/dNTP analogues by chemical substitutions to nucleotide analogues.

PubMed: 33356231
DOI: 10.1021/acs.jmedchem.0c01747

実験手法

X-RAY DIFFRACTION (2.75 Å)