3QLH

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

Summary for 3QLH

• Entry DOI: 10.2210/pdb3qlh/pdb
• Descriptor: 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)
• Functional Keywords: rnase h inhibitor, structure-based drug design, tropolone derivatives, divalent cation chelator, non-nucleoside rt inhibitor, transferase, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Human immunodeficiency virus type 1 (HIV-1); More
• Cellular location: 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
• Total number of polymer chains: 2
• Total formula weight: 114195.65

Authors

Himmel, D.M.,Wojtak, K.,Bauman, J.D.,Arnold, E. (deposition date: 2011-02-02, release date: 2011-12-21, Last modification date: 2024-03-13)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.7 Å)