5XN0

HIV-1 reverse transcriptase Q151M:DNA binary complex

5XN0 の概要

• エントリーDOI: 10.2210/pdb5xn0/pdb
• 関連するPDBエントリー: 4ZHR
• 関連するBIRD辞書のPRD_ID: PRD_900003
• 分子名称: Pol protein, 38-MER DNA aptamer, beta-D-fructofuranose-(2-1)-alpha-D-glucopyranose, ... (6 entities in total)
• 機能のキーワード: hiv-1, hbv, reverse transcriptase, drug resistance, drug sensitivity, transferase-dna complex, transferase/dna
• 由来する生物種: Human immunodeficiency virus 1; 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 256041.64

構造登録者

Yasutake, Y.,Tamura, N.,Hayashi, H.,Maeda, K. (登録日: 2017-05-17, 公開日: 2018-02-07, 最終更新日: 2023-11-22)

主引用文献

Yasutake, Y.,Hattori, S.I.,Hayashi, H.,Matsuda, K.,Tamura, N.,Kohgo, S.,Maeda, K.,Mitsuya, H.
HIV-1 with HBV-associated Q151M substitution in RT becomes highly susceptible to entecavir: structural insights into HBV-RT inhibition by entecavir.
Sci Rep, 8:1624-1624, 2018

PubMed Abstract: Hepatitis B virus (HBV) reverse transcriptase (RT) is essential for viral replication and is an important drug target. Nonetheless, the notorious insolubility of HBV RT has hindered experimental structural studies and structure-based drug design. Here, we demonstrate that a Q151M substitution alone at the nucleotide-binding site (N-site) of human immunodeficiency virus type-1 (HIV-1) RT renders HIV-1 highly sensitive to entecavir (ETV), a potent nucleoside analogue RT inhibitor (NRTI) against HBV. The results suggest that Met151 forms a transient hydrophobic interaction with the cyclopentyl methylene of ETV, a characteristic hydrophobic moiety of ETV. We thus solved the crystal structures of HIV-1 RT:DNA complex with bound dGTP or ETV-triphosphate (ETV-TP). The structures revealed that ETV-TP is accommodated at the N-site slightly apart from the ribose ring of the 3'-end nucleotide, compared to the position of bound dGTP and previously reported NRTI/dNTP. In addition, the protruding methylene group of bound ETV-TP directly pushes the side-chain of Met184 backward. Met184 is a key residue that confers ETV resistance upon substitution with smaller Ile/Val. These results provide novel insights into NRTI binding to the N-site and further provide important clues for the development of novel anti-HBV/HIV-1 RT inhibitors to overcome critical drug resistance.

PubMed: 29374261
DOI: 10.1038/s41598-018-19602-9

実験手法

X-RAY DIFFRACTION (2.596 Å)