Mon, 22/10/2018 - 14:30
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Campus Homburg, CIPMM, Seminar Room (1st Floor)

Prof. Dr. Dr. Hans-Robert Kalbitzer
Institute for Biophysics and Physical Chemistry, University Regensburg

Detection of Rare Conformational States of Proteins by High Pressure NMR Spectroscopy

Rare conformational states are often crucial for the understanding of function and catalytic mechanism of biological macromolecules. In addition to the elucidation of the classical three-dimensional (ground state) structure of proteins there is gaining interest in the dynamic properties of proteins and the characterization of intrinsic equilibria between conformers. Applying high pressure to such biomolecules allows the shift of intrinsic conformational equilibria up to the stabilization of higher energy conformers (“excited” states) according to their smaller specific volume. The application of high pressures up to 300 MPa combined with NMR spectroscopy as detection method allows the investigation of such intrinsic equilibria of conformations and the characterization of rare conformers up to atomic resolution, respectively. Rare (exited) conformational states allow the definition of a novel type of allosteric inhibitors, the intrinsic allosteric inhibitors, in drug design. Rare conformational states could be detected in two different pathogenic proteins, in the protooncogene Ras (rat sarcoma) and the amyloid β peptide Aβ. Point mutations of Ras are found in more than 30 % of all human tumors, Aβ fibrillary deposits (amyloids) are found in the brains of humans with Alzheimer disease. We show that intrinsic allosteric inhibitors recognizing a specific rare state can really be found for the two proteins. In case of the Ras protein we could design a small compound that suppresses the signal transduction that is enhanced in tumor cells with oncogenic Ras mutants. In Ab we could identify D-eneatiomeric peptides that inhibit fibrillation. The binding surface of one of these inhibitors RD2D3 could be mapped on a specific three-dimensional structure of Aβ.

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