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Publication Abstract from PubMed

Formation of the mature HIV-1 reverse transcriptase (RT) p66/p51 heterodimer requires subunit-specific processing of the p66/p66' homodimer precursor. Since the ribonuclease H (RH) domain contains an occult cleavage site located near its center, cleavage must occur either prior to folding or subsequent to unfolding. Recent NMR studies have identified a slow, subunit-specific RH domain unfolding process proposed to result from a residue tug-of-war between the polymerase and RH domains on the functionally inactive, p66' subunit. Here, we describe a structural comparison of the isolated RH domain with a domain swapped RH dimer that reveals several intrinsically destabilizing characteristics of the isolated domain that facilitate excursions of Tyr427 from its binding pocket and separation of helices B and D. These studies provide independent support for the subunit-selective RH domain unfolding pathway in which instability of the Tyr427 binding pocket facilitates its release followed by domain transfer, acting as a trigger for further RH domain destabilization and subsequent unfolding. As further support for this pathway, NMR studies demonstrate that addition of an RH active site-directed isoquinolone ligand retards the subunit-selective RH' domain unfolding behavior of the p66/p66' homodimer. This study demonstrates the feasibility of directly targeting RT maturation with therapeutics.

Unfolding the HIV-1 reverse transcriptase RNase H domain - how to lose a molecular tug-of-war.,Zheng X, Pedersen LC, Gabel SA, Mueller GA, DeRose EF, London RE Nucleic Acids Res. 2016 Feb 29;44(4):1776-88. doi: 10.1093/nar/gkv1538. Epub 2016, Jan 14. PMID:26773054^[1]

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