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Identification of drivers for the metamorphic transition of HIV-1 reverse transcriptase.

Identification of drivers for the metamorphic transition of HIV-1 reverse transcriptase.
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Zheng X, Mueller GA, Kiim K, Perera L, DeRose EF, London RE,


Zheng X, Mueller GA, Kiim K, Perera L, DeRose EF, London RE, (click to view)

Zheng X, Mueller GA, Kiim K, Perera L, DeRose EF, London RE,

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The Biochemical journal 2017 08 15() pii 10.1042/BCJ20170480

Abstract

Recent structural characterizations of the p51 and p66 monomers has established an important starting point for understanding the maturation pathway of the HIV-1 reverse transcriptase p66/p51 heterodimer. This process requires a metamorphic transition of the polymerase domain leading to formation of a p66/p66′ homodimer that exists as a structural heterodimer. In order to better understand the drivers for this metamorphic transition, we have performed NMR studies of (15)N-labeled RT216 – a construct that includes the fingers and most of the palm domains. These studies are consistent with the conclusion that the p66 monomer exists as a spring-loaded complex. Initial dissociation of the fingers/palm:connection complex allows the fingers/palm to adopt an alternate, more stable structure, reducing the rate of re-association and facilitating subsequent maturation steps. One of the drivers for an initial extension of the fingers/palm domains is identified as a straightening of helix E relative to its conformation in the monomer by eliminating a bend of ~ 50° near residue Phe160. NMR and CD data also are consistent with the conclusion that a hydrophobic surface of palm domain that becomes exposed after the initial dissociation, as well as the intrinsic conformational preferences of the palm domain C-terminal segment, facilitate formation of the b-sheet structure that is unique to the active polymerase subunit. Spectral comparisons based on (15)N-labeled constructs are all consistent with previous structural conclusions based on studies of (13)C-methyl-labeled constructs.

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