3qin

Publication Abstract from PubMed

Human immunodeficiency virus (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 (1.4A-2.1A) crystal structures were determined with isolated RNase H domain and 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.

Structural and Binding Analysis of Pyrimidinol Carboxylic Acid and N-hydroxy Quinazolinedione HIV-1 RNase H Inhibitors.,Lansdon EB, Liu Q, Leavitt SA, Balakrishnan M, Perry JK, Lancaster-Moyer C, Kutty N, Liu X, Squires NH, Watkins WJ, Kirschberg TA Antimicrob Agents Chemother. 2011 Apr 4. PMID:21464257^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.