Determine the structural basis of splicing modulation by small molecules
EMSL Project ID
51786
Abstract
Aberrant pre-mRNA splicing contributes to 10-15 % of genetic disorders, including Spinal Muscular Atrophy (SMA). SMA is a potentially lethal neurodegenerative disorder caused by loss of function mutations or deletions in the gene SMN1. SMN2, a duplication of SMN1, has a weak 5' splice site (ss) that cause exon 7 skipping which generates a truncated and unstable protein. A small molecule Risdiplam promotes exon 7 inclusion and it has been recently approved by the FDA for the treatment of SMA. Another class of small molecule represented by Branaplam can also promote the recognition of the same weak 5' ss in spite of a completely different structure from Risdiplam. Our goal in this project is to determine how these two very different classes of small molecules promote weak 5' ss recognition using cryo-EM. These results will facilitate future effort on designing small molecules targeting other weak 5' in genetic diseases.
Project Details
Start Date
2020-12-15
End Date
2021-03-17
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members