Join us for the fall semester ASRC-CCNY Seminar Series in Biochemistry, Biophysics and Biodesign every Wednesday at noon! This week’s speaker, Julien Orts, Assistant Professor in the Division of Pharmaceutical Chemistry at the University of Vienna, Austria, will be presenting a talk titled,
“Lead Generation without an X-Ray Crystal Structure: An NMR Method to Probe Protein- Ligand Complexes.”
ABSTRACT 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. The two major limitations of its application to drug research are (i) the availability of a similar protein structure, and (ii) obtaining well-diffracting crystals of the ligand-protein complexes of interest. While nowadays the first point is often not a limitation anymore, obtaining well-diffracting crystals may be difficult. In such situations structure determination of protein-ligand complexes by liquid-state NMR is a good option. Unfortunately, the established standard structure determination protocol is in general time-consuming, and a shortcut using available structural data as in the case of MR in X-ray crystallography is not available.
Here, we present NMR2 (NMR Molecular Replacement), a MR-like approach in NMR to determine the structures of the binding pockets of ligands at atomic resolution. The calculation of structures of protein-ligand complexes relies on the collection of unassigned semi-quantitative inter-molecular NOE distance restraints and on previously solved structures. The NMR2 method uses a high throughput structure calculation protocol, rather than a docking- scoring simulation. It is fast since it requires only a few days of measuring time and bypasses the time-consuming sequential assignment steps for the protein.
We will present multiple NMR2 applications covering several ligand topologies ranging from peptidomimetic to small molecules that bind strongly or weakly to protein receptors. We also report how NMR2 can make use of partially labelled protein using methyl-specific isotope labelling. Finally, we will present our latest methodology development to further advance the technique. Our findings demonstrate that NMR2 may open an avenue for the fast and robust determination of the binding pocket structure of ligand-protein complexes at atomic resolution.
*Dr. Orts will be giving this talk via ZOOM. The Zoom broadcast may be viewed remotely, or in the ASRC Main Auditorium. For non-CUNY in-person attendees: advance registration is required; please contact Hyacinth Camillieri at email@example.com no later than Monday, Nov. 27 for entry to the ASRC.
To view this seminar:
Meeting ID: 966 7763 1144