3QLH

HIV-1 Reverse Transcriptase in Complex with Manicol at the RNase H Active Site and TMC278 (Rilpivirine) at the NNRTI Binding Pocket

3QLH の概要

• エントリーDOI: 10.2210/pdb3qlh/pdb
• 分子名称: reverse transcriptase/ribonuclease H, (2S)-5,7-dihydroxy-9-methyl-2-(prop-1-en-2-yl)-1,2,3,4-tetrahydro-6H-benzo[7]annulen-6-one, 4-{[4-({4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl}amino)pyrimidin-2-yl]amino}benzonitrile, ... (8 entities in total)
• 機能のキーワード: rnase h inhibitor, structure-based drug design, tropolone derivatives, divalent cation chelator, non-nucleoside rt inhibitor, transferase, hydrolase-inhibitor complex, hydrolase/inhibitor
• 由来する生物種: Human immunodeficiency virus type 1 (HIV-1); 詳細
• 細胞内の位置: Gag-Pol polyprotein: Host cell membrane; Lipid-anchor. Matrix protein p17: Virion membrane; Lipid- anchor . Capsid protein p24: Virion . Nucleocapsid protein p7: Virion . Reverse transcriptase/ribonuclease H: Virion . Integrase: Virion : P03366 P03366
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 114195.65

構造登録者

Himmel, D.M.,Wojtak, K.,Bauman, J.D.,Arnold, E. (登録日: 2011-02-02, 公開日: 2011-12-21, 最終更新日: 2024-03-13)

主引用文献

Chung, S.,Himmel, D.M.,Jiang, J.K.,Wojtak, K.,Bauman, J.D.,Rausch, J.W.,Wilson, J.A.,Beutler, J.A.,Thomas, C.J.,Arnold, E.,Le Grice, S.F.
Synthesis, activity, and structural analysis of novel alpha-hydroxytropolone inhibitors of human immunodeficiency virus reverse transcriptase-associated ribonuclease H.
J.Med.Chem., 54:4462-4473, 2011

PubMed Abstract: The α-hydroxytroplone, manicol (5,7-dihydroxy-2-isopropenyl-9-methyl-1,2,3,4-tetrahydro-benzocyclohepten-6-one), potently and specifically inhibits ribonuclease H (RNase H) activity of human immunodeficiency virus reverse transcriptase (HIV RT) in vitro. However, manicol was ineffective in reducing virus replication in culture. Ongoing efforts to improve the potency and specificity over the lead compound led us to synthesize 14 manicol derivatives that retain the divalent metal-chelating α-hydroxytropolone pharmacophore. These efforts were augmented by a high resolution structure of p66/p51 HIV-1 RT containing the nonnucleoside reverse transcriptase inhibitor (NNRTI), TMC278 and manicol in the DNA polymerase and RNase H active sites, respectively. We demonstrate here that several modified α-hydroxytropolones exhibit antiviral activity at noncytotoxic concentrations. Inclusion of RNase H active site mutants indicated that manicol analogues can occupy an additional site in or around the DNA polymerase catalytic center. Collectively, our studies will promote future structure-based design of improved α-hydroxytropolones to complement the NRTI and NNRTI currently in clinical use.

PubMed: 21568335
DOI: 10.1021/jm2000757

実験手法

X-RAY DIFFRACTION (2.7 Å)