The goal of this project is to elucidate the structural basis for biological activity of untranslated RNAs, including their interactions with other RNAs and with proteins. Specifically we will focus on the structure and chemistry of the hepatitis delta virus (HDV) ribozyme, and the mechanism of protein binding and translocation by the signal recognition particle (SRP) RNA-protein complex. Building on our recently- determined structures of both the HDV ribozyme and the RNA-protein """"""""core"""""""" of the SRP, we will solve and analyze structures of complexes containing substrates analogs.
Specific aims for the next five years include: 1. Solve crystal structures of the HDV genomic ribozyme precursor containing non-cleavable analogs at the scissile bond. These structures will be essential to understanding the possible catalytic role of active-site nucleotides, as well as for determining whether metal ions are directly involved in the chemical step of the ribozyme reaction. 2. Determine the structure of the anti-genomic HDV ribozyme in both the precursor and cleaved forms. The secondary structures of the genomic and anti-genomic RNAs are similar but not identical, leading to questions about their evolution that will be answered by structural comparisons. Furthermore, comparison of active site components and conforms will likely elucidate the essential elements for catalysis. 3. Solve crystals of functional complexes of the signal recognition particle (SRP) from E. coli This efforts extends our recent determination of the SRP RNA-protein core structures at 1.55 A resolution.
We aim to determine the role of the RNA in signal peptide recognition and protein translocation.
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