Dynamic bulge nucleotides in the KSHV PAN ENE triple helix provide a unique binding platform for small molecule ligands

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dc.contributor.authorSwain, Monalisa
dc.contributor.authorAgeeli, Abeer A
dc.contributor.authorKasprzak, Wojciech K
dc.contributor.authorLi, Mi
dc.contributor.authorMiller, Jennifer T
dc.contributor.authorSztuba-Solinska, Joanna
dc.contributor.authorSchneekloth, John S
dc.contributor.authorKoirala, Deepak
dc.contributor.authorPiccirili,  Joseph
dc.contributor.authorFraboni, Americo J
dc.contributor.authorMurelli, Ryan P
dc.contributor.authorWlodawer, Alexander
dc.contributor.authorShapiro, Bruce A
dc.contributor.authorBaird, Nathan
dc.contributor.authorGrice, Stuart F J Le 
dc.date.accessioned2022-01-20T17:36:20Z
dc.date.available2022-01-20T17:36:20Z
dc.date.issued2021-12-16
dc.description.abstractCellular and virus-coded long non-coding (lnc) RNAs support multiple roles related to biological and pathological processes. Several lncRNAs sequester their 3′ termini to evade cellular degradation machinery, thereby supporting disease progression. An intramolecular triplex involving the lncRNA 3′ terminus, the element for nuclear expression (ENE), stabilizes RNA transcripts and promotes persistent function. Therefore, such ENE triplexes, as presented here in Kaposi's sarcoma-associated herpesvirus (KSHV) polyadenylated nuclear (PAN) lncRNA, represent targets for therapeutic development. Towards identifying novel ligands targeting the PAN ENE triplex, we screened a library of immobilized small molecules and identified several triplex-binding chemotypes, the tightest of which exhibits micromolar binding affinity. Combined biophysical, biochemical, and computational strategies localized ligand binding to a platform created near a dinucleotide bulge at the base of the triplex. Crystal structures of apo (3.3 Å) and ligand-soaked (2.5 Å) ENE triplexes, which include a stabilizing basal duplex, indicate significant local structural rearrangements within this dinucleotide bulge. MD simulations and a modified nucleoside analog interference technique corroborate the role of the bulge and the base of the triplex in ligand binding. Together with recently discovered small molecules that reduce nuclear MALAT1 lncRNA levels by engaging its ENE triplex, our data supports the potential of targeting RNA triplexes with small molecules.en_US
dc.description.sponsorshipSearle Funds at The Chicago Community; National Cancer Institute (Intramural Research Program, ZIA-BC011585- 07); Chicago Biomedical Consortium; National Heart, Lung, and Blood Institute [K22-HL121113A]; National Institute of General Medical Sciences [R01GM102489, SC1GM111158]; Frederick National Laboratory for Cancer Research [HHSN75N91019D00024]; University of the Sciences; Saudi Arabian Cultural Mission and Jazan University. Funding for open access charge: University of the Sciences (Start-up funds to N. Baird).en_US
dc.description.urihttps://academic.oup.com/nar/article/49/22/13179/6454283en_US
dc.format.extent15 pagesen_US
dc.genrejournal articlesen_US
dc.identifierdoi:10.13016/m2gf44-iyrf
dc.identifier.citationMonalisa Swain, Abeer A Ageeli, Wojciech K Kasprzak, Mi Li, Jennifer T Miller, Joanna Sztuba-Solinska, John S Schneekloth, Deepak Koirala, Joseph Piccirili, Americo J Fraboni, Ryan P Murelli, Alexander Wlodawer, Bruce A Shapiro, Nathan Baird, Stuart F J Le Grice, Dynamic bulge nucleotides in the KSHV PAN ENE triple helix provide a unique binding platform for small molecule ligands, Nucleic Acids Research, Volume 49, Issue 22, 16 December 2021, Pages 13179–13193, https://doi.org/10.1093/nar/gkab1170en_US
dc.identifier.urihttps://doi.org/10.1093/nar/gkab1170
dc.identifier.urihttp://hdl.handle.net/11603/24036
dc.language.isoen_USen_US
dc.publisherOxford University Pressen_US
dc.relation.isAvailableAtThe University of Maryland, Baltimore County (UMBC)
dc.relation.ispartofUMBC Chemistry & Biochemistry Department Collection
dc.relation.ispartofUMBC Faculty Collection
dc.rightsThis work was written as part of one of the author's official duties as an Employee of the United States Government and is therefore a work of the United States Government. In accordance with 17 U.S.C. 105, no copyright protection is available for such works under U.S. Law.en_US
dc.rightsPublic Domain Mark 1.0*
dc.rights.urihttp://creativecommons.org/publicdomain/mark/1.0/*
dc.titleDynamic bulge nucleotides in the KSHV PAN ENE triple helix provide a unique binding platform for small molecule ligandsen_US
dc.typeTexten_US
dcterms.creatorhttps://orcid.org/0000-0001-6424-3173en_US

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