campus seminar: Enhancing NMR signals to study proteins and small molecules
campus seminar
- Datum: 10.11.2021
- Uhrzeit: 11:00 - 12:00
- Vortragende(r): Riza Dervisoglu
- Research Group Solid State NMR
- Ort: Max-Planck-Institut für biophysikalische Chemie (MPIBPC)
- Raum: Manfred Eigen Hall & Online
- Gastgeber: Loren Andreas, Alex Faesen, Aljaz Godec, Stefan Karpitschka, Juliane Liepe, Alexander Stein, David Zwicker, Sonja Lorenz, Oleksiy Kovtun, Grazvydas Lukinavicius, Marieke Oudelaar, Knut Heidemann,Stefan Glöggler
- Kontakt: stefan.gloeggler@mpibpc.mpg.de
Nuclear magnetic resonance (NMR) plays an essential role in natural science and medicine. In spite of the tremendous utility associated with the small energies detected, the most severe limitation is the low signal-to-noise ratio. Dynamic nuclear polarization (DNP), a technique based on transfer of polarization from electron or para-hydrogen to nuclear spins, has emerged as a tool to enhance sensitivity of NMR.
Cross effect DNP in solid samples at 100 K is by now a well-established method. Room-temperature, liquid state DNP 13C and 1H signal enhancements in organic small molecules is a challenging pursuit. Here, we demonstrate the capabilities of such NMR signal enhancement methods on proteins and small molecules, as well as report on the development in these challenging techniques.
The small molecule anle138b, a clinical drug candidate, was shown to modulate protein aggregation processes relevant in neurodegenerative diseases. In animal models, the progression of these diseases is slowed down upon administration of anle138b leading to reduced protein misfolding, increased lifespan and improved performance scores. Yet the structural mechanism by which anle138b acts remains to be characterized in detail. Here we probe the interaction of anle138b with the protein α-synuclein for both fibrils, as well as an intermediate species trapped early in the fibrilization process. The small central pyrazole moiety of anle138b is detected in close proximity to the protein backbone using dynamic nuclear polarization enhanced magic-angle spinning NMR, which also quenches fibrillization due to the 100 K temperature. While the drug candidate anle138b binds to both fibril and intermediate, the binding mode appears to be different, based on the 13C NMR shifts of the protein.
Cross effect DNP in solid samples at 100 K is by now a well-established method. Room-temperature, liquid state DNP 13C and 1H signal enhancements in organic small molecules is a challenging pursuit. Here, we demonstrate the capabilities of such NMR signal enhancement methods on proteins and small molecules, as well as report on the development in these challenging techniques.
The small molecule anle138b, a clinical drug candidate, was shown to modulate protein aggregation processes relevant in neurodegenerative diseases. In animal models, the progression of these diseases is slowed down upon administration of anle138b leading to reduced protein misfolding, increased lifespan and improved performance scores. Yet the structural mechanism by which anle138b acts remains to be characterized in detail. Here we probe the interaction of anle138b with the protein α-synuclein for both fibrils, as well as an intermediate species trapped early in the fibrilization process. The small central pyrazole moiety of anle138b is detected in close proximity to the protein backbone using dynamic nuclear polarization enhanced magic-angle spinning NMR, which also quenches fibrillization due to the 100 K temperature. While the drug candidate anle138b binds to both fibril and intermediate, the binding mode appears to be different, based on the 13C NMR shifts of the protein.