6ELI

Structure of HIV-1 reverse transcriptase (RT) in complex with rilpivirine and an RNase H inhibitor XZ462

Summary for 6ELI

• Entry DOI: 10.2210/pdb6eli/pdb
• Related: 4G1Q
• Descriptor: reverse transcriptase, Gag-Pol polyprotein, 4-{[4-({4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl}amino)pyrimidin-2-yl]amino}benzonitrile, ... (8 entities in total)
• Functional Keywords: p51/p66, hetero dimer, nnrti, ribonuclease h inhibitor, nonnucleoside inhibitor, aids, hiv, r278474, diarylpyrimidine, dapy, dna recombination, dna polymerase, endonuclease, hydrolase, multifunctional, enzyme, transferase, hydrolase-inhibitor complex
• Biological source: Human immunodeficiency virus type 1 BH10; More
• Total number of polymer chains: 2
• Total formula weight: 115049.35

Authors

Das, K.,Arnold, E. (deposition date: 2017-09-29, release date: 2018-04-11, Last modification date: 2024-01-17)

Primary citation

Boyer, P.L.,Smith, S.J.,Zhao, X.Z.,Das, K.,Gruber, K.,Arnold, E.,Burke, T.R.,Hughes, S.H.
Developing and Evaluating Inhibitors against the RNase H Active Site of HIV-1 Reverse Transcriptase.
J. Virol., 92:-, 2018

PubMed Abstract: We tested three compounds for their ability to inhibit the RNase H (RH) and polymerase activities of HIV-1 reverse transcriptase (RT). A high-resolution crystal structure (2.2 Å) of one of the compounds showed that it chelates the two magnesium ions at the RH active site; this prevents the RH active site from interacting with, and cleaving, the RNA strand of an RNA-DNA heteroduplex. The compounds were tested using a variety of substrates: all three compounds inhibited the polymerase-independent RH activity of HIV-1 RT. Time-of-addition experiments showed that the compounds were more potent if they were bound to RT before the nucleic acid substrate was added. The compounds significantly inhibited the site-specific cleavage required to generate the polypurine tract (PPT) RNA primer that initiates the second strand of viral DNA synthesis. The compounds also reduced the polymerase activity of RT; this ability was a result of the compounds binding to the RH active site. These compounds appear to be relatively specific; they do not inhibit either RNase HI or human RNase H2. The compounds inhibit the replication of an HIV-1-based vector in a one-round assay, and their potencies were only modestly decreased by mutations that confer resistance to integrase strand transfer inhibitors (INSTIs), nucleoside analogs, or nonnucleoside RT inhibitors (NNRTIs), suggesting that their ability to block HIV replication is related to their ability to block RH cleavage. These compounds appear to be useful leads that can be used to develop more potent and specific compounds. Despite advances in HIV-1 treatment, drug resistance is still a problem. Of the four enzymatic activities found in HIV-1 proteins (protease, RT polymerase, RT RNase H, and integrase), only RNase H has no approved therapeutics directed against it. This new target could be used to design and develop new classes of inhibitors that would suppress the replication of the drug-resistant variants that have been selected by the current therapeutics.

PubMed: 29643235
DOI: 10.1128/JVI.02203-17

Experimental method

X-RAY DIFFRACTION (2.2 Å)