4E1N

Crystal Structure of HIV-1 Integrase with a non-catayltic site inhibitor

4E1N の概要

• エントリーDOI: 10.2210/pdb4e1n/pdb
• 関連するPDBエントリー: 4E1M
• 分子名称: HIV-1 integrase, (2S)-tert-butoxy[4-(8-fluoro-5-methyl-3,4-dihydro-2H-chromen-6-yl)-2-methylquinolin-3-yl]ethanoic acid (3 entities in total)
• 機能のキーワード: hiv-1, integrase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Human immunodeficiency virus type 1 (HIV-1)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 18842.20

構造登録者

Lansdon, E.B. (登録日: 2012-03-06, 公開日: 2012-04-25, 最終更新日: 2024-10-30)

主引用文献

Tsiang, M.,Jones, G.S.,Niedziela-Majka, A.,Kan, E.,Lansdon, E.B.,Huang, W.,Hung, M.,Samuel, D.,Novikov, N.,Xu, Y.,Mitchell, M.,Guo, H.,Babaoglu, K.,Liu, X.,Geleziunas, R.,Sakowicz, R.
New Class of HIV-1 Integrase (IN) Inhibitors with a Dual Mode of Action.
J.Biol.Chem., 287:21189-21203, 2012

PubMed Abstract: tert-Butoxy-(4-phenyl-quinolin-3-yl)-acetic acids (tBPQA) are a new class of HIV-1 integrase (IN) inhibitors that are structurally distinct from IN strand transfer inhibitors but analogous to LEDGINs. LEDGINs are a class of potent antiviral compounds that interacts with the lens epithelium-derived growth factor (LEDGF) binding pocket on IN and were identified through competition binding against LEDGF. LEDGF tethers IN to the host chromatin and enables targeted integration of viral DNA. The prevailing understanding of the antiviral mechanism of LEDGINs is that they inhibit LEDGF binding to IN, which prevents targeted integration of HIV-1. We showed that in addition to the properties already known for LEDGINs, the binding of tBPQAs to the IN dimer interface inhibits IN enzymatic activity in a LEDGF-independent manner. Using the analysis of two long terminal repeat junctions in HIV-infected cells, we showed that the inhibition by tBPQAs occurs at or prior to the viral DNA 3'-processing step. Biochemical studies revealed that this inhibition operates by compound-induced conformational changes in the IN dimer that prevent proper assembly of IN onto viral DNA. For the first time, tBPQAs were demonstrated to be allosteric inhibitors of HIV-1 IN displaying a dual mode of action: inhibition of IN-viral DNA assembly and inhibition of IN-LEDGF interaction.

PubMed: 22535962
DOI: 10.1074/jbc.M112.347534

実験手法

X-RAY DIFFRACTION (2 Å)