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SUMMARY:Computational analyses of RNA repeat expansions causing genetic di
 sease - Dr. Ilyas Yildirim\, Deparment of Chemistry\, University of Cambri
 dge
DTSTART:20141010T110000Z
DTEND:20141010T120000Z
UID:TALK54452@talks.cam.ac.uk
CONTACT:Dr. Judith B. Rommel
DESCRIPTION:Trinucleotide and tetranucleotide repeat disorders are genetic
  inheritable diseases caused by mutations in DNA where the repeats in cert
 ain genes exceed the normal size. Once the repeats are transcribed\, mRNA 
 folds into a hairpin with repeating CXG (X = C\, A\, G\, U) or CCUG motifs
 \, which either attract cytoplasmic multiprotein complexes or translate in
 to toxic polyQ proteins and cause the disease. These mRNA repeats have 1×
 1 or 2×2 internal loops\, which make them ideal targets for pharmacologic
  development. Yet\, the dynamic nature of RNA loops presents a significant
  challenge to obtaining reasonable predictions for targeting RNA repeats w
 ith small molecules. Two important results from our recent studies provide
  a point of entry into this challenging problem. First\, we found that 1×
 1 AA internal loops in RNA CAG repeat expansions are dynamic and can form 
 multiple different stable conformations\; and second\, we found that targe
 ting 1×1 UU and 2×2 CU/UC internal loops with a small molecules produced
  complex structural changes in the RNA loop conformations with lowest free
  energy structures corresponding to one of the local minimum states predic
 ted for 1×1 AA internal loops. These results suggest that RNA internal lo
 ops have multiple different free energy minimum states\, which could be do
 minated with small molecules upon binding. 
LOCATION:Pfizer Lecture Theatre\, Department of Chemistry
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