Dynamic ensemble of HIV-1 RRE stem IIB reveals non-native conformations that disrupt the Rev-binding site.
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
26 07 2019
26 07 2019
Historique:
accepted:
07
06
2019
revised:
21
05
2019
received:
17
12
2018
pubmed:
15
6
2019
medline:
7
1
2020
entrez:
15
6
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31199872
pii: 5519168
doi: 10.1093/nar/gkz498
pmc: PMC6649712
doi:
Substances chimiques
rev Gene Products, Human Immunodeficiency Virus
0
rev protein, Human Immunodeficiency Virus-1
0
Magnesium
I38ZP9992A
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
7105-7117Informations de copyright
© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.
Références
Proc Natl Acad Sci U S A. 2014 Jul 1;111(26):9485-90
pubmed: 24979799
Science. 1996 Sep 13;273(5281):1547-51
pubmed: 8703216
Nucleic Acids Res. 1992 Dec 25;20(24):6465-72
pubmed: 1282702
Biochemistry. 1994 Mar 15;33(10):2741-7
pubmed: 8130185
Nat Commun. 2018 Feb 9;9(1):606
pubmed: 29426922
J Mol Recognit. 2016 May;29(5):199-209
pubmed: 26620599
J Mol Biol. 1997 Mar 14;266(5):950-62
pubmed: 9086273
Chem Rev. 2006 May;106(5):1700-19
pubmed: 16683750
Cell. 1989 Dec 1;59(5):789-95
pubmed: 2686839
Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):7366-70
pubmed: 1871141
Cell. 1991 Apr 19;65(2):241-8
pubmed: 2015625
Cell. 1991 Oct 4;67(1):169-78
pubmed: 1913815
Angew Chem Int Ed Engl. 2016 Dec 19;55(51):15869-15872
pubmed: 27860024
Eur J Biochem. 1995 Jun 15;230(3):1073-87
pubmed: 7601138
Nature. 2015 Mar 19;519(7543):315-20
pubmed: 25762137
Biochemistry. 1991 Jun 4;30(22):5449-58
pubmed: 2036413
Nucleic Acids Res. 2017 Aug 21;45(14):e134
pubmed: 28609788
Biochemistry. 1994 May 10;33(18):5357-66
pubmed: 8180157
Annu Rev Biochem. 2014;83:441-66
pubmed: 24606137
Nucleic Acids Res. 2011 May;39(10):4340-51
pubmed: 21252295
J Mol Biol. 1996 May 24;258(5):763-77
pubmed: 8637008
J Mol Biol. 2017 Mar 10;429(5):697-714
pubmed: 28153748
Curr Opin Struct Biol. 2015 Feb;30:112-124
pubmed: 25727496
Nucleic Acids Res. 2018 Jan 9;46(1):314-323
pubmed: 29177466
Nat Rev Microbiol. 2014 May;12(5):341-54
pubmed: 24736794
Nature. 2015 Oct 29;526(7575):672-7
pubmed: 26416753
J Mol Biol. 1996 Dec 20;264(5):863-77
pubmed: 9000617
J Magn Reson. 2014 Jul;244:18-29
pubmed: 24819426
Cell. 1993 Sep 24;74(6):969-78
pubmed: 8402886
Proc Natl Acad Sci U S A. 2000 May 9;97(10):5107-12
pubmed: 10792052
Proc Natl Acad Sci U S A. 1997 Nov 11;94(23):12366-71
pubmed: 9356455
Cell Rep. 2018 Mar 20;22(12):3240-3250
pubmed: 29562180
Cell. 1993 Jun 4;73(5):1031-40
pubmed: 7684657
Nucleic Acids Res. 2007;35(5):1698-713
pubmed: 17311812
J Am Chem Soc. 2006 Jan 18;128(2):410-1
pubmed: 16402818
EMBO J. 1992 Mar;11(3):1119-29
pubmed: 1547776
Mol Cell. 2008 Sep 26;31(6):824-34
pubmed: 18922466
RNA. 2014 Nov;20(11):1815-26
pubmed: 25183835
Elife. 2014 Aug 27;3:e03656
pubmed: 25163983
Cell Chem Biol. 2016 Sep 22;23(9):1077-1090
pubmed: 27593111
J Mol Biol. 1994 Aug 12;241(2):193-207
pubmed: 8057359
Chemistry. 2015 Aug 10;21(33):11634-11643
pubmed: 26237536
Cell. 1996 Oct 4;87(1):115-25
pubmed: 8858154
Nat Immunol. 2017 Aug 22;18(9):962-972
pubmed: 28829444
Nat Chem Biol. 2011 Jun 26;7(8):553-9
pubmed: 21706033
J Virol. 1991 Apr;65(4):2131-4
pubmed: 2002556
J Biomol NMR. 1995 Nov;6(3):277-93
pubmed: 8520220
Nucleic Acids Res. 2015 May 19;43(9):4676-86
pubmed: 25855816
Nat Struct Mol Biol. 2018 May;25(5):425-434
pubmed: 29728655
J Am Chem Soc. 2006 Aug 2;128(30):9909-18
pubmed: 16866550
J Mol Biol. 1990 Apr 5;212(3):437-40
pubmed: 2182883
Science. 1991 Dec 13;254(5038):1598-603
pubmed: 1749933
Psychon Bull Rev. 2004 Feb;11(1):192-6
pubmed: 15117008
Cell. 2009 Feb 20;136(4):604-9
pubmed: 19239882
Proc Natl Acad Sci U S A. 2009 Feb 3;106(5):1404-8
pubmed: 19164515
Nat Chem Biol. 2017 Sep;13(9):968-974
pubmed: 28719589
Nat Rev Genet. 2004 Jul;5(7):522-31
pubmed: 15211354
Nat Struct Mol Biol. 2016 Sep;23(9):803-10
pubmed: 27478929
Bioorg Med Chem. 2001 May;9(5):1097-113
pubmed: 11377168
Q Rev Biophys. 2016 Jan;49:e7
pubmed: 27266715
Proc Natl Acad Sci U S A. 1986 Apr;83(8):2402-6
pubmed: 3458205
J Biomol NMR. 1995 Dec;6(4):375-89
pubmed: 8563466
Cell. 2018 Jul 12;174(2):377-390.e20
pubmed: 29961580
J Mol Biol. 2000 Jan 28;295(4):711-7
pubmed: 10656783
Nature. 2012 Nov 29;491(7426):724-8
pubmed: 23041928
Proc Natl Acad Sci U S A. 1991 Feb 1;88(3):683-7
pubmed: 1992459
RNA Biol. 2012 Jan;9(1):6-11
pubmed: 22258145
Biochemistry. 1996 Oct 22;35(42):13689-96
pubmed: 8885849
Proc Natl Acad Sci U S A. 1970 Jan;65(1):19-26
pubmed: 5263750
Nature. 2018 Feb 8;554(7691):195-201
pubmed: 29420478
Biochem Pharmacol. 2016 May 1;107:14-28
pubmed: 26896646
Annu Rev Pharmacol Toxicol. 2016;56:123-40
pubmed: 26514201
Nat Commun. 2016 Jun 13;7:ncomms11768
pubmed: 27292179
Cell. 2014 Mar 27;157(1):77-94
pubmed: 24679528
Viruses. 2015 Jun 12;7(6):3053-75
pubmed: 26075509
J Am Chem Soc. 2009 Mar 25;131(11):3818-9
pubmed: 19243182
Methods Enzymol. 2015;558:39-73
pubmed: 26068737
Nature. 2008 Mar 6;452(7183):51-5
pubmed: 18322526
Expert Opin Drug Discov. 2011 Jan;6(1):17-32
pubmed: 22328899
Cell. 1990 Feb 23;60(4):675-83
pubmed: 2406030
Elife. 2014 Dec 08;3:e04120
pubmed: 25486594
Cell. 1991 Nov 1;67(3):529-36
pubmed: 1934059
Nature. 2012 Feb 15;482(7385):322-30
pubmed: 22337051
Biopolymers. 2003 Sep;70(1):103-19
pubmed: 12925996
Proc Natl Acad Sci U S A. 2010 Jul 13;107(28):12481-6
pubmed: 20616058
Cell. 2013 Oct 24;155(3):594-605
pubmed: 24243017
Curr Opin Struct Biol. 2015 Feb;30:134-146
pubmed: 25765780
Nat Struct Mol Biol. 2010 Nov;17(11):1337-42
pubmed: 20953181
Nucleic Acids Res. 2016 Apr 20;44(7):2987-99
pubmed: 26969733
J Biol Chem. 1999 Jun 18;274(25):17452-63
pubmed: 10364175
Nature. 1989 Mar 16;338(6212):254-7
pubmed: 2784194
J Am Chem Soc. 2005 Jan 19;127(2):713-21
pubmed: 15643897