5DZM

HIV-1 Reverse Transcriptase RH domain

Summary for 5DZM

• Entry DOI: 10.2210/pdb5dzm/pdb
• Descriptor: Ribonuclease H (2 entities in total)
• Functional Keywords: hiv, ribonuclease, unfolding, reverse transcriptase, hydrolase
• Biological source: Human immunodeficiency virus 1
• Total number of polymer chains: 4
• Total formula weight: 61105.11

Authors

Pedersen, L.C.,London, R.E.,Gabel, S.A.,Zheng, X.H. (deposition date: 2015-09-25, release date: 2016-05-11, Last modification date: 2023-09-27)

Primary citation

Zheng, X.,Pedersen, L.C.,Gabel, S.A.,Mueller, G.A.,DeRose, E.F.,London, R.E.
Unfolding the HIV-1 reverse transcriptase RNase H domain - how to lose a molecular tug-of-war.
Nucleic Acids Res., 44:1776-1788, 2016

PubMed 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-selective RH' domain unfolding behavior of the p66/p66' homodimer. This study demonstrates the feasibility of directly targeting RT maturation with therapeutics.

PubMed: 26773054
DOI: 10.1093/nar/gkv1538

Experimental method

X-RAY DIFFRACTION (2.05 Å)