Journal
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
Volume 55, Issue 6, Pages 2905-2915Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/AAC.01594-10
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- Office of Science, Office of Basic Energy Sciences, U.S. Department of Energy [DE-AC02-05CH11231]
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HIV-1 RNase H breaks down the intermediate RNA-DNA hybrids during reverse transcription, requiring two divalent metal ions for activity. Pyrimidinol carboxylic acid and N-hydroxy quinazolinedione inhibitors were designed to coordinate the two metal ions in the active site of RNase H. High-resolution (1.4 angstrom to 2.1 angstrom) crystal structures were determined with the isolated RNase H domain and reverse transcriptase (RT), which permit accurate assessment of the metal and water environment at the active site. The geometry of the metal coordination suggests that the inhibitors mimic a substrate state prior to phosphodiester catalysis. Surface plasmon resonance studies confirm metal-dependent binding to RNase H and demonstrate that the inhibitors do not bind at the polymerase active site of RT. Additional evaluation of the RNase H site reveals an open protein surface with few additional interactions to optimize active-site inhibitors.
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