Structural and binding analysis of pyrimidinol carboxylic acid and N-hydroxy quinazolinedione HIV-1 RNase H inhibitors.

Article Details

Citation

Lansdon EB, Liu Q, Leavitt SA, Balakrishnan M, Perry JK, Lancaster-Moyer C, Kutty N, Liu X, Squires NH, Watkins WJ, Kirschberg TA

Structural and binding analysis of pyrimidinol carboxylic acid and N-hydroxy quinazolinedione HIV-1 RNase H inhibitors.

Antimicrob Agents Chemother. 2011 Jun;55(6):2905-15. doi: 10.1128/AAC.01594-10. Epub 2011 Apr 4.

PubMed ID
21464257 [ View in PubMed
]
Abstract

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 A to 2.1 A) 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.

DrugBank Data that Cites this Article

Polypeptides
NameUniProt ID
Reverse transcriptase/RNaseHQ72547Details