About event
X-ray crystallography molecular replacement (MR) is a highly versatile tool for the detailed characterization of lead compound and binding modes in the pharmaceutical industry. MR is one of the most successful approaches in structural biology. MR stands out as one of the most successful approaches in structural biology.
I will present our work on establishing a similar MR approach in NMR spectroscopy, known as NMR2 (NMR Molecular Replacement). NMR2 is an MR-like method in NMR that aims to determine the structures of ligand binding pockets at atomic resolution. The NMR2 approach employs a high-throughput structure calculation protocol instead of a docking-scoring simulation. It is characterized by its speed, requiring only a few days of measuring time, and it circumvents the time-consuming steps of sequential assignment for the protein.
During the presentation, we will showcase multiple applications of NMR2, encompassing various ligand topologies, ranging from peptidomimetics to small molecules that bind strongly or weakly to protein receptors. Additionally, we will discuss how NMR2 can effectively utilize partially labeled proteins through methyl-specific isotope labeling. Lastly, we will present our latest methodology development aimed at further advancing this technique. Our findings demonstrate that NMR2 holds the potential to open a fast and robust avenue for determining the binding pocket structure of ligand-protein complexes at atomic resolution.
The physical chemistry frame for studying intra- and inter-molecular interactions is thermodynamics. The extent to which two molecules interact is dictated by the Gibbs energy change (ΔG) of the interactions, which is composed of enthalpic (ΔH) and entropic (ΔS) terms.
X-ray crystallographic and NMR structures provide a detailed description of the static interactions associated with enthalpic contributions. However, up to now, the entropic components remain difficult to address experimentally.
I will present our strategy using NMR to study protein thermodynamics. It is anticipated that quantitative thermodynamic measurements within molecules and molecular complexes will open a new avenue in the fundamental understanding of how atomistic mechanism create a function.
More information
Julien Orts was trained in Physics & Biophysics and graduated in 2010 jointly from the Max Planck Institute for Biophysical Chemistry and the European Molecular Biology Laboratory under the guidance of Prof. Carlogmano and Prof. Griesinger. During that time, he developed the INPHARMA method that can experimentally assess the quality of docking poses of fragments and drugs in the receptor-binding site using only unlabeled protein (ug) from cell extra. Julien joined the BioNMR laboratory at the ETH Zurich led by Prof. Riek, first as a post-doc and then as a junior group leader, where he developed new NMR methods, such as the exact NOEs that improve the NOE accuracy by order of magnitude.
In 2021, he relocated to the University of Vienna, joining the Division of Pharmaceutical Chemistry as an Assistant Professor. Since 2024, he has held the position of Associate Professor and scientific director of the NMR facility. His laboratory specializes in Drug Discovery through advanced NMR methods, encompassing integrated approaches for rapid determination of protein-ligand complex structures, NMR-based drug design, protein allostery, and the thermodynamics of protein-protein and protein-ligand interactions.
