5VH8

Structure and dynamics of RNA repeat expansions that cause Huntington's Disease and myotonic dystrophy type 1

Summary for 5VH8

• Entry DOI: 10.2210/pdb5vh8/pdb
• Related: 5VH7
• NMR Information: BMRB: 30283
• Descriptor: RNA (5'-R(*GP*AP*CP*CP*UP*GP*CP*UP*GP*CP*UP*GP*GP*UP*C)-3') (1 entity in total)
• Functional Keywords: cug repeat, triplet repeat, myotonic dystrophy, repeat expansion, uu pair, rna
• Biological source: Homo sapiens
• Total number of polymer chains: 2
• Total formula weight: 9521.70

Authors

Chen, J.L.,VanEtten, D.M.,Fountain, M.A.,Yildirim, I.,Disney, M.D. (deposition date: 2017-04-12, release date: 2017-06-28, Last modification date: 2024-05-01)

Primary citation

Chen, J.L.,VanEtten, D.M.,Fountain, M.A.,Yildirim, I.,Disney, M.D.
Structure and Dynamics of RNA Repeat Expansions That Cause Huntington's Disease and Myotonic Dystrophy Type 1.
Biochemistry, 56:3463-3474, 2017

PubMed Abstract: RNA repeat expansions cause a host of incurable, genetically defined diseases. The most common class of RNA repeats consists of trinucleotide repeats. These long, repeating transcripts fold into hairpins containing 1 × 1 internal loops that can mediate disease via a variety of mechanism(s) in which RNA is the central player. Two of these disorders are Huntington's disease and myotonic dystrophy type 1, which are caused by r(CAG) and r(CUG) repeats, respectively. We report the structures of two RNA constructs containing three copies of a r(CAG) [r(3×CAG)] or r(CUG) [r(3×CUG)] motif that were modeled with nuclear magnetic resonance spectroscopy and simulated annealing with restrained molecular dynamics. The 1 × 1 internal loops of r(3×CAG) are stabilized by one-hydrogen bond (cis Watson-Crick/Watson-Crick) AA pairs, while those of r(3×CUG) prefer one- or two-hydrogen bond (cis Watson-Crick/Watson-Crick) UU pairs. Assigned chemical shifts for the residues depended on the identity of neighbors or next nearest neighbors. Additional insights into the dynamics of these RNA constructs were gained by molecular dynamics simulations and a discrete path sampling method. Results indicate that the global structures of the RNA are A-form and that the loop regions are dynamic. The results will be useful for understanding the dynamic trajectory of these RNA repeats but also may aid in the development of therapeutics.

PubMed: 28617590
DOI: 10.1021/acs.biochem.7b00252

Experimental method

SOLUTION NMR