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Viruses 2016, 8(10), 260; doi:10.3390/v8100260

Structural Maturation of HIV-1 Reverse Transcriptase—A Metamorphic Solution to Genomic Instability

Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA
Academic Editor: Alexander Ploss
Received: 1 July 2016 / Accepted: 12 September 2016 / Published: 27 September 2016
View Full-Text   |   Download PDF [8033 KB, uploaded 27 September 2016]   |  

Abstract

Human immunodeficiency virus 1 (HIV-1) reverse transcriptase (RT)—a critical enzyme of the viral life cycle—undergoes a complex maturation process, required so that a pair of p66 precursor proteins can develop conformationally along different pathways, one evolving to form active polymerase and ribonuclease H (RH) domains, while the second forms a non-functional polymerase and a proteolyzed RH domain. These parallel maturation pathways rely on the structural ambiguity of a metamorphic polymerase domain, for which the sequence–structure relationship is not unique. Recent nuclear magnetic resonance (NMR) studies utilizing selective labeling techniques, and structural characterization of the p66 monomer precursor have provided important insights into the details of this maturation pathway, revealing many aspects of the three major steps involved: (1) domain rearrangement; (2) dimerization; and (3) subunit-selective RH domain proteolysis. This review summarizes the major structural changes that occur during the maturation process. We also highlight how mutations, often viewed within the context of the mature RT heterodimer, can exert a major influence on maturation and dimerization. It is further suggested that several steps in the RT maturation pathway may provide attractive targets for drug development. View Full-Text
Keywords: HIV-1 reverse transcriptase; reverse transcriptase maturation pathway; metamorphic protein; RNase H domain; subunit-specific RNase H domain unfolding; structural heterodimer HIV-1 reverse transcriptase; reverse transcriptase maturation pathway; metamorphic protein; RNase H domain; subunit-specific RNase H domain unfolding; structural heterodimer
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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London, R.E. Structural Maturation of HIV-1 Reverse Transcriptase—A Metamorphic Solution to Genomic Instability. Viruses 2016, 8, 260.

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