4QAG

Structure of a dihydroxycoumarin active-site inhibitor in complex with the RNASE H domain of HIV-1 reverse transcriptase

Replaces:  4JE2

Summary for 4QAG

• Entry DOI: 10.2210/pdb4qag/pdb
• Related: 3IFJ 3IG1 3K2P 3QLH 4G1Q
• Descriptor: Reverse transcriptase/ribonuclease H, MANGANESE (II) ION, (7,8-dihydroxy-2-oxo-2H-chromen-4-yl)acetic acid, ... (4 entities in total)
• Functional Keywords: rnase h inhibitor, structure-based drug design, active site, transferase, dihydroxycoumarin analogs, dihydroxy-benzopyrone derivatives, divalent cation chelator, aids, reverse transcriptase, protein-inhibitor complex, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Human immunodeficiency virus type 1 (HIV-1)
• Cellular location: 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
• Total number of polymer chains: 2
• Total formula weight: 30121.44

Authors

Himmel, D.M.,Ho, W.C.,Arnold, E. (deposition date: 2014-05-04, release date: 2014-06-04, Last modification date: 2023-09-20)

Primary citation

Himmel, D.M.,Myshakina, N.S.,Ilina, T.,Van Ry, A.,Ho, W.C.,Parniak, M.A.,Arnold, E.
Structure of a Dihydroxycoumarin Active-Site Inhibitor in Complex with the RNase H Domain of HIV-1 Reverse Transcriptase and Structure-Activity Analysis of Inhibitor Analogs.
J.Mol.Biol., 426:2617-2631, 2014

PubMed Abstract: Human immunodeficiency virus (HIV) encodes four essential enzymes: protease, integrase, reverse transcriptase (RT)-associated DNA polymerase, and RT-associated ribonuclease H (RNase H). Current clinically approved anti-AIDS drugs target all HIV enzymatic activities except RNase H, which has proven to be a very difficult target for HIV drug discovery. Our high-throughput screening activities identified the dihydroxycoumarin compound F3284-8495 as a specific inhibitor of RT RNase H, with low micromolar potency in vitro. Optimization of inhibitory potency can be facilitated by structural information about inhibitor-target binding. Here, we report the crystal structure of F3284-8495 bound to the active site of an isolated RNase H domain of HIV-1 RT at a resolution limit of 1.71Å. From predictions based on this structure, compounds were obtained that showed improved inhibitory activity. Computational analysis suggested structural alterations that could provide additional interactions with RT and thus improve inhibitory potency. These studies established proof of concept that F3284-8495 could be used as a favorable chemical scaffold for development of HIV RNase H inhibitors.

PubMed: 24840303
DOI: 10.1016/j.jmb.2014.05.006

Experimental method

X-RAY DIFFRACTION (1.712 Å)