Molecular recognition of poly(A) by small ligands: an alternative method of analysis reveals nanomolar, cooperative and shape-selective binding.

TitleMolecular recognition of poly(A) by small ligands: an alternative method of analysis reveals nanomolar, cooperative and shape-selective binding.
Publication TypeJournal Article
Year of Publication2009
AuthorsCetinkol, OPersil, Hud, NV
JournalNucleic Acids Res
Volume37
Issue2
Pagination611-21
Date Published2009 Feb
ISSN1362-4962
KeywordsBenzimidazoles, Berberine, Berberine Alkaloids, Ellipticines, Ligands, Poly A
Abstract

A few drug-like molecules have recently been found to bind poly(A) and induce a stable secondary structure (T(m) approximately 60 degrees C), even though this RNA homopolymer is single-stranded in the absence of a ligand. Here, we report results from experiments specifically designed to explore the association of small molecules with poly(A). We demonstrate that coralyne, the first small molecule discovered to bind poly(dA), binds with unexpectedly high affinity (K(a) >10(7) M(-1)), and that the crescent shape of coralyne appears necessary for poly(A) binding. We also show that the binding of similar ligands to poly(A) can be highly cooperative. For one particular ligand, at least six ligand molecules are required to stabilize the poly(A) self-structure at room temperature. This highly cooperative binding produces very sharp transitions between unstructured and structured poly(A) as a function of ligand concentration. Given the fact that junctions between Watson-Crick and A.A duplexes are tolerated, we propose that poly(A) sequence elements and appropriate ligands could be used to reversibly drive transitions in DNA and RNA-based molecular structures by simply diluting/concentrating a sample about the poly(A)-ligand 'critical concentration'. The ligands described here may also find biological or medicinal applications, owing to the 3'-polyadenylation of mRNA in living cells.

DOI10.1093/nar/gkn977
Alternate JournalNucleic Acids Res.
PubMed ID19073699
PubMed Central IDPMC2632892