DC 10: Lead finding and structural characterization of the 5’-UTR of ompA of A. baumannii using fragment screening and application of paramagnetic NMR restraints
Research field: (paramagnetic) NMR, organic synthesis, RNA, structure determination, machine learning, fragment based screening.
Main content
PhD project description:
First, we will apply the fragment-based NMR screening method to the 5’-UTR of ompA (at Saverna). For hit expansion, we will use AI methods developed at Saverna to select compounds from large combinatorial compound libraries which will subsequently be tested for binding to the target RNA. The same method will also be used to select follow-up compounds of fragment hits for the remaining targets in the network.
Second, we will determine the structure of 5’-UTR of ompA. The target consists of 131 nucleotides and contains several secondary structure elements. To determine the structure of such a large RNAs in solution by NMR spectroscopy we will develop new methods using paramagnetic restraints. This will also require to synthesize new paramagnetic tags and conjugate them to fragments and/or RNA to refine the RNA-ligand interactions. The obtained PCS will provide long-range (>100 Å) distance and angular restraints that will be very helpful in connecting the secondary structure elements and determine the overall 3D structure of the RNA.
Subsequently, we will probe the influence of ligands developed in WP2 on the dynamics of the target using NMR spectroscopy. We will also collaborate with DC14 on compound design for this target.
PhD candidate: Sviatlana Kashyrskaya
Supervisor: Daniel Häussinger
Host institute: Department of Chemistry, University of Basel, Switzerland
Secondments planned: Uppsala University structure determination using cryo-EM.
Doctoral program: Doctoral Studies University of Basel.
Doctoral Studies | University of Basel (unibas.ch)
