4OJR

Crystal Structure of the HIV-1 Integrase catalytic domain with GSK1264

4OJR の概要

• エントリーDOI: 10.2210/pdb4ojr/pdb
• 分子名称: HIV-1 Integrase, (2S)-tert-butoxy[4-(8-fluoro-5-methyl-3,4-dihydro-2H-chromen-6-yl)-2-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl]ethanoic acid, CACODYLATE ION, ... (5 entities in total)
• 機能のキーワード: viral dna integration, dna binding, ledgf binding, viral protein
• 由来する生物種: Human immunodeficiency virus type 1 (HIV-1)
• 細胞内の位置: Matrix protein p17: Virion (Potential). Capsid protein p24: Virion (Potential). Nucleocapsid protein p7: Virion (Potential). Reverse transcriptase/ribonuclease H: Virion (Potential). Integrase: Virion (Potential): P03366
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 18763.05

構造登録者

Gupta, K.,Brady, T.,Dyer, B.,Hwang, Y.,Male, F.,Nolte, R.T.,Wang, L.,Velthuisen, E.,Jeffrey, J.,Van Duyne, G.,Bushman, F.D. (登録日: 2014-01-21, 公開日: 2014-06-11, 最終更新日: 2024-02-28)

主引用文献

Gupta, K.,Brady, T.,Dyer, B.M.,Malani, N.,Hwang, Y.,Male, F.,Nolte, R.T.,Wang, L.,Velthuisen, E.,Jeffrey, J.,Van Duyne, G.D.,Bushman, F.D.
Allosteric Inhibition of Human Immunodeficiency Virus Integrase: LATE BLOCK DURING VIRAL REPLICATION AND ABNORMAL MULTIMERIZATION INVOLVING SPECIFIC PROTEIN DOMAINS.
J.Biol.Chem., 289:20477-20488, 2014

PubMed Abstract: HIV-1 replication in the presence of antiviral agents results in evolution of drug-resistant variants, motivating the search for additional drug classes. Here we report studies of GSK1264, which was identified as a compound that disrupts the interaction between HIV-1 integrase (IN) and the cellular factor lens epithelium-derived growth factor (LEDGF)/p75. GSK1264 displayed potent antiviral activity and was found to bind at the site occupied by LEDGF/p75 on IN by x-ray crystallography. Assays of HIV replication in the presence of GSK1264 showed only modest inhibition of the early infection steps and little effect on integration targeting, which is guided by the LEDGF/p75-IN interaction. In contrast, inhibition of late replication steps was more potent. Particle production was normal, but particles showed reduced infectivity. GSK1264 promoted aggregation of IN and preformed LEDGF/p75-IN complexes, suggesting a mechanism of inhibition. LEDGF/p75 was not displaced from IN during aggregation, indicating trapping of LEDGF/p75 in aggregates. Aggregation assays with truncated IN variants revealed that a construct with catalytic and C-terminal domains of IN only formed an open polymer associated with efficient drug-induced aggregation. These data suggest that the allosteric inhibitors of IN are promising antiviral agents and provide new information on their mechanism of action.

PubMed: 24904063
DOI: 10.1074/jbc.M114.551119

実験手法

X-RAY DIFFRACTION (1.82 Å)