Unfolding the HIV-1 reverse transcriptase RNase H domain--how to lose a molecular tug-of-war

Nucleic Acids Research
Xunhai ZhengRobert E London

Abstract

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-sel...Continue Reading

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Citations

Aug 16, 2017·The Biochemical Journal·Xunhai ZhengRobert E London
Dec 19, 2020·International Journal of Molecular Sciences·Tatiana V IlinaRieko Ishima
Oct 3, 2019·ACS Infectious Diseases·Zhaoyong XiRieko Ishima

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