5EW4

Crystal structure of C9ORF72 Antisense CCCCGG repeat RNA associated with Lou Gehrig's disease and frontotemporal dementia, crystallized with Sr2+

Summary for 5EW4

• Entry DOI: 10.2210/pdb5ew4/pdb
• Related: 5EW7
• Descriptor: RNA (5'-R(*CP*CP*CP*CP*GP*GP*CP*CP*CP*CP*GP*GP*CP*CP*CP*CP*GP*GP*CP*CP*CP*C)-3'), POTASSIUM ION, STRONTIUM ION, ... (6 entities in total)
• Functional Keywords: repeat expansion disorder, genetic disease, rna
• Biological source: Homo sapiens
• Total number of polymer chains: 2
• Total formula weight: 14341.94

Authors

Tomchick, D.R.,Dodd, D.W.,Gagnon, K.T.,Corey, D.R. (deposition date: 2015-11-20, release date: 2016-02-24, Last modification date: 2024-03-06)

Primary citation

Dodd, D.W.,Tomchick, D.R.,Corey, D.R.,Gagnon, K.T.
Pathogenic C9ORF72 Antisense Repeat RNA Forms a Double Helix with Tandem C:C Mismatches.
Biochemistry, 55:1283-1286, 2016

PubMed Abstract: Expansion of a GGGGCC/CCCCGG repeat sequence in the first intron of the C9ORF72 gene is a leading cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). In this combined disorder, called c9FTD/ALS, the expansion is bidirectionally transcribed into sense and antisense repeat RNA associated with disease. To better understand the role of C9ORF72 repeat RNA in molecular disease pathology, we determined crystal structures of a [(CCCCGG)3(CCCC)] model antisense repeat RNA to 1.47 Å resolution. The RNA structure was an A-form-like double helix composed of repeating and regularly spaced tandem C:C mismatch pairs that perturbed helical geometry and surface charge. Solution studies revealed a preference for A-form-like helical conformations as the repeat number increased. Results provide a structural starting point for rationalizing the contribution of repeat RNA to c9FTD/ALS molecular disease mechanisms and for developing molecules to target C9ORF72 repeat RNA as potential therapeutics.

PubMed: 26878348
DOI: 10.1021/acs.biochem.6b00136

Experimental method

X-RAY DIFFRACTION (1.47 Å)