A PhD position is offered at the University of Lille (France), starting 1 October 2023.
Integrative Structural Biology team (CNRS EMR9002)
Risk Factors and Molecular Determinants of Aging-Related Diseases (RID-AGE — Univ. Lille, Inserm, Institut Pasteur de Lille)
Ultrahigh resolution NMR to unveil the impact of post-translational modifications in disordered proteins
Thesis supervisor: Dr. Davy Sinnaeve
For many biomacromolecules (disordered proteins, but also glycans, oligonucleotides), their biological function cannot be understood on the basis of a single conformation, but as an ensemble of different transient conformations. Uncovering the molecular mechanisms of these functions requires a detailed mapping of the full ensemble of conformers. Liquid-state NMR spectroscopy is the leading experimental technique to study such flexible systems, as it provides information at an atom-specific level that is sensitive to both structure and molecular motion. Unfortunately, the fast structural averaging also strongly reduces chemical shift dispersion, resulting in low spectral resolution and complicating interpretation of spectral data.
In our research group, we are developing new NMR experiments to facilitate the extraction of spectral information for both small molecules and macromolecular compounds. These methods are mainly inspired by so-called “pure shift” homodecoupling NMR methods, which can be used to edit the presence of homonuclear couplings in the spectrum. Particularly, we are interested in developing methods that exploit these methods to accurately measure scalar coupling and residual dipolar couplings (RDCs), which are powerful reporters of molecular structure and dynamics. To learn more about our research and that of the rest of the team, please visit our website: https://bsi-lille.cnrs.fr/la-recherche/
This PhD project will focus heavily on NMR methodology, developing experiments with the aim of obtaining structure-sensitive spectral information. The intended application will be on biomedically relevant disordered proteins whose conformational ensemble changes upon post-translational modification (PTM), such as serine phosphorylation. Such PTMs are a biochemical means to regulate the properties of the protein, such as the binding affinities to other proteins. Towards deciphering mechanism by which post-translational modifications regulate protein function, detailed structural information is in demand.
Profile of the candidate
Candidates should have a background in chemistry or physics, with a strong affinity for analytical or physical chemistry. An enthusiastic, pro-active and co-operative approach is expected, as well the ability to work both independently and as part of a team. The daily activities will mainly consist out of research, but it is also expected that the candidate participates in internal seminars, courses, local and international scientific events, and in the supervision of Master or internship students. Collaboration and interaction with other researchers within the team will be encouraged. The candidate is expected to present his/her work both through written reports and in oral presentations, meaning good communication skills are required. Professional communication with the supervisor and other members of the team will be in English.
How to apply
To apply, please send a motivation letter and your CV to Davy Sinnaeve (email@example.com). Please also provide contact details of your Master thesis or internship supervisor as a reference.
Do not hesitate to get in touch for more information.
Facilities & Team
The Integrative Structural Biology CNRS research group investigates the structural basis and molecular mechanism underlying protein biological functions, and the impact of their deregulation in human diseases. In particular, we are interested in intrinsically disordered proteins involved in proteinopathies. At the heart of our work are biophysical multidisciplinary methods for characterizing the structure of proteins, as well as the interactions between them, such as Nuclear Magnetic Resonance spectroscopy, X-ray crystallography and cryo-electron microscopy. Our research is essentially fundamental, but we remain attentive to its application to the development of new therapeutic approaches, the evaluation of the therapeutic potential of various compounds from small molecules to nanobodies, and the study of the mode of action of bioactive molecules.
The group has access to state-of-the-art liquid NMR instrumentation in Lille, including a recently installed 1.2 GHz spectrometer (Avance NEO, cryoprobe), a 900 MHz (Avance NEO, cryoprobe), an 800 MHz (Avance NEO), and a 600 MHz (Avance III HD, cryoprobe). Furthermore, we are part of Infranalytics (https://infranalytics.cnrs.fr/), a national research infrastructure network of NMR, EPR and FT-ICR MS laboratories. This network connects us to all the French specialists in High resolution NMR spectroscopy and allows easy access to additional high field spectrometers and specific hardware. The laboratory possesses state-of-the-art facilities for molecular biology, biochemistry and cell biology.
Some relevant references
Sinnaeve, D., Ilgen, J., Di Pietro, M. E., Primozic, J. J., Schmidts, V., Thiele, C. M., and Luy, B. (2020) Probing Long-Range Anisotropic Interactions: a General and Sign-Sensitive Strategy to Measure 1H-1H Residual Dipolar Couplings as a Key Advance for Organic Structure Determination. Angew. Chem. Int. Ed. 59, 5316-5320
Open access: https://hal.science/hal-02538220v1/document
Sinnaeve, D., Foroozandeh, M., Nilsson, M., and Morris, G. A. (2016) A General Method for Extracting Individual Coupling Constants from Crowded 1H NMR Spectra. Angew. Chem. Int. Ed. 55, 1090-1093
Open access: https://onlinelibrary.wiley.com/doi/full/10.1002/anie.201508691
Sinnaeve, D. (2021) Selective Homonuclear 2D J-resolved Spectroscopy eMagRes 9, 267-281, https://doi.org/10.1002/9780470034590.emrstm1544
Open access: https://cnrs.hal.science/hal-03322837v1/document
Sinnaeve, D., Dinclaux, M., Cahoreau, E., Millard, P., Portais, J. C., Letisse, F., Lippens G. (2018) Improved Isotopic Profiling by Pure Shift Heteronuclear 2D J-Resolved NMR Spectroscopy Anal. Chem. 90, 4025-4031
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Dr. Davy Sinnaeve
Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167 - RID-AGE - Risk Factors and Molecular Determinants of Aging-Related Diseases, F-59000 Lille, France
CNRS, EMR9002 - Integrative Structural Biology, F-59000 Lille, France
Postal address: 50, Avenue de Halley, Campus CNRS de la Haute Borne, F-59658 Villeneuve d'Ascq, France
Tel.: +33 3 62 53 17 05