ESR2: Jonathan Lefèbre

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Host Organization
Molecular Drug Targeting Group
Department of Pharmaceutical Sciences
University of Vienna

Supervisor
Prof. Christoph Rademacher
Biophysical characterization of allosteric interactions using NMR spectroscopy
C-type lectin receptors (CLRs) constitute a large superfamily of glycan binding proteins that are involved in diverse physiological processes, including adaptive and innate immunity. Despite the growing pharmaceutical interest, only a limited number of CLR-targeted molecular probes have been identified. Primarily, this can be explained by the low druggability of the often shallow and hydrophilic nature of the CLR’s primary binding site. Yet, recent insights indicate the existence of druggable secondary sites as well as ligand-induced allosteric modulation of CLRs. My PhD project aims at elucidating mechanisms of allosteric modulation of CLRs via secondary sites and how these can be exploited for the discovery of small molecule probes that modulate receptor activity. The project will be guided by the following objectives:
  1. Identification and characterization of potential allosteric sites and allosteric modulators from predictive computational methods and biophysical screening.
  2. Application of ligand-observed NMR methods for screening and druggability assessment of target proteins. 
  3. Binding site identification and validation using protein-observed NMR methods using either 15N labeled protein or incorporation of fluorinated amino acids into larger receptor complexes. 
  4. Identification of allosteric signal transmission pathways in proteins using CHESPA and related methods as well as incorporation site specific labels.
Brief Scientific Bio
I studied Biochemistry at the Freie Universität Berlin (Germany), where I graduated with a M. Sc. degree in December 2020. During my studies, I additionally got the opportunity to work as a research intern at Shanghai Humantech Biotechnology (Shanghai, PR China) and the Max Planck Institute of Colloids and Interfaces (Potsdam, Germany), where I also completed my master thesis with a focus on NMR spectroscopy of protein-ligand interactions. In 2021, I joined the Molecular Drug Targeting Group at the University of Vienna (Austria) as a Ph.D. candidate to work on allosteric modulation of C-type lectin receptors under the supervision of Prof. Dr. Rademacher.
This project has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 956314.
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