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Dynamic ensemble of HIV-1 RRE stem IIB reveals non-native conformations that disrupt the Rev-binding site.

Publication ,  Journal Article
Chu, C-C; Plangger, R; Kreutz, C; Al-Hashimi, HM
Published in: Nucleic Acids Res
July 26, 2019

The HIV-1 Rev response element (RRE) RNA element mediates the nuclear export of intron containing viral RNAs by forming an oligomeric complex with the viral protein Rev. Stem IIB and nearby stem II three-way junction nucleate oligomerization through cooperative binding of two Rev molecules. Conformational flexibility at this RRE region has been shown to be important for Rev binding. However, the nature of the flexibility has remained elusive. Here, using NMR relaxation dispersion, including a new strategy for directly observing transient conformational states in large RNAs, we find that stem IIB alone or when part of the larger RREII three-way junction robustly exists in dynamic equilibrium with non-native excited state (ES) conformations that have a combined population of ∼20%. The ESs disrupt the Rev-binding site by changing local secondary structure, and their stabilization via point substitution mutations decreases the binding affinity to the Rev arginine-rich motif (ARM) by 15- to 80-fold. The ensemble clarifies the conformational flexibility observed in stem IIB, reveals long-range conformational coupling between stem IIB and the three-way junction that may play roles in cooperative Rev binding, and also identifies non-native RRE conformational states as new targets for the development of anti-HIV therapeutics.

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Published In

Nucleic Acids Res

DOI

EISSN

1362-4962

Publication Date

July 26, 2019

Volume

47

Issue

13

Start / End Page

7105 / 7117

Location

England

Related Subject Headings

  • rev Gene Products, Human Immunodeficiency Virus
  • Nucleic Acid Conformation
  • Nuclear Magnetic Resonance, Biomolecular
  • Magnesium
  • HIV-1
  • Genes, env
  • Developmental Biology
  • Binding Sites
  • Amino Acid Sequence
  • 41 Environmental sciences
 

Citation

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Chu, C.-C., Plangger, R., Kreutz, C., & Al-Hashimi, H. M. (2019). Dynamic ensemble of HIV-1 RRE stem IIB reveals non-native conformations that disrupt the Rev-binding site. Nucleic Acids Res, 47(13), 7105–7117. https://doi.org/10.1093/nar/gkz498
Chu, Chia-Chieh, Raphael Plangger, Christoph Kreutz, and Hashim M. Al-Hashimi. “Dynamic ensemble of HIV-1 RRE stem IIB reveals non-native conformations that disrupt the Rev-binding site.Nucleic Acids Res 47, no. 13 (July 26, 2019): 7105–17. https://doi.org/10.1093/nar/gkz498.
Chu C-C, Plangger R, Kreutz C, Al-Hashimi HM. Dynamic ensemble of HIV-1 RRE stem IIB reveals non-native conformations that disrupt the Rev-binding site. Nucleic Acids Res. 2019 Jul 26;47(13):7105–17.
Chu, Chia-Chieh, et al. “Dynamic ensemble of HIV-1 RRE stem IIB reveals non-native conformations that disrupt the Rev-binding site.Nucleic Acids Res, vol. 47, no. 13, July 2019, pp. 7105–17. Pubmed, doi:10.1093/nar/gkz498.
Chu C-C, Plangger R, Kreutz C, Al-Hashimi HM. Dynamic ensemble of HIV-1 RRE stem IIB reveals non-native conformations that disrupt the Rev-binding site. Nucleic Acids Res. 2019 Jul 26;47(13):7105–7117.
Journal cover image

Published In

Nucleic Acids Res

DOI

EISSN

1362-4962

Publication Date

July 26, 2019

Volume

47

Issue

13

Start / End Page

7105 / 7117

Location

England

Related Subject Headings

  • rev Gene Products, Human Immunodeficiency Virus
  • Nucleic Acid Conformation
  • Nuclear Magnetic Resonance, Biomolecular
  • Magnesium
  • HIV-1
  • Genes, env
  • Developmental Biology
  • Binding Sites
  • Amino Acid Sequence
  • 41 Environmental sciences