title: Myotonic dystrophy type 1 RNA crystal structures reveal heterogeneous 1 × 1 nucleotide UU internal loop conformations.
abstract: RNA internal loops often display a variety of conformations in solution. Herein, we visualize conformational heterogeneity in the context of the 5'CUG/3'GUC repeat motif present in the RNA that causes myotonic dystrophy type 1 (DM1). Specifically, two crystal structures of a model DM1 triplet repeating construct, 5'r[UUGGGC(CUG)(3)GUCC](2), refined to 2.20 and 1.52 Å resolution are disclosed. Here, differences in the orientation of the 5' dangling UU end between the two structures induce changes in the backbone groove width, which reveals that noncanonical 1 × 1 nucleotide UU internal loops can display an ensemble of pairing conformations. In the 2.20 Å structure, CUGa, the 5' UU forms a one hydrogen-bonded pair with a 5' UU of a neighboring helix in the unit cell to form a pseudoinfinite helix. The central 1 × 1 nucleotide UU internal loop has no hydrogen bonds, while the terminal 1 × 1 nucleotide UU internal loops each form a one-hydrogen bond pair. In the 1.52 Å structure, CUGb, the 5' UU dangling end is tucked into the major groove of the duplex. While the canonically paired bases show no change in base pairing, in CUGb the terminal 1 × 1 nucleotide UU internal loops now form two hydrogen-bonded pairs. Thus, the shift in the major groove induced by the 5' UU dangling end alters noncanonical base patterns. Collectively, these structures indicate that 1 × 1 nucleotide UU internal loops in DM1 may sample multiple conformations in vivo. This observation has implications for the recognition of this RNA, and other repeating transcripts, by protein and small molecule ligands.
authors: Department of Chemistry, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, United States.
authors: Amit
authors: A
authors: Kumar
authors: HaJeung
authors: H
authors: Park
authors: Pengfei
authors: P
authors: Fang
authors: Raman
authors: R
authors: Parkesh
authors: Min
authors: M
authors: Guo
authors: Kendall W
authors: KW
authors: Nettles
authors: Matthew D
authors: MD
authors: Disney
mesh_terms: D020029:Base Pairing; D001483:Base Sequence; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D009223:Myotonic Dystrophy / Q000235:genetics* / Q000378:metabolism*; D009690:Nucleic Acid Conformation; D012313:RNA / Q000737:chemistry* / Q000235:genetics*; D055672:Static Electricity
chemical_list: D012313:RNA