Structural biology and biophysical characterization of stabilizing molecules acting on 14-3-3 PPIs
Modulation of Protein-Protein Interactions (PPIs) with small-molecules is one of the most promising and fast growing areas in Chemical Biology and Drug Discovery. Whereas inhibition of PPIs is a well-documented strategy, the opposite approach of small-molecule stabilization of PPIs has not been followed systematically in spite of the fact that it theoretically represents a more readily achievable goal. This gap will be addressed in the TASPPI consortium through investigation of 14-3-3 adapter proteins, which act as “hubs” by forming 1:1 complexes with several hundred partner proteins in human cells. An alteration to a 14-3-3 PPI is implicated in a number of diseases ranging from cancer and neurodegeneration to inflammation and metabolic syndromes. In the Innovative Training Network TASPPI (Targeted Stabilization of Protein-Protein Interactions) we aim in a consortium of 5 universities (Dundee, Eindhoven, Leeds, Lille, Prague, Siena), 3 pharma companies (AstraZeneca, GSK, UCB), and 2 SMEs (LDC, Taros) to identify and optimize small-molecule 14-3-3 PPI stabilizers as novel tools for basic research and starting points for drug development. The position described here will be based primarily at UCB’s research site in Slough, United Kingdom with a 3-6 month secondment with the Ottmann group at the Technical University of Eindhoven. The successful candidate will work together with 12 other PhDs within TASPPI and will be included in a network-wide training programme. As part of the MSCA mobility requirements candidates are eligible for this position when they have spent no more than 12 months of their main activity (work, study) in the last three years in The UK.
- Purification of 14-3-3 proteins and their target protein partners
- Co-crystallization of 14-3-3 proteins in complex with protein partners, peptides and small molecules
- Set-up of screens (e.g. FRET) to identify both stabilisers and disruptors of 14-3-3/ protein interactions
- X-ray crystallography fragment-based ligand identification
- Biophysical characterization of complexes by Surface Plasmon Resonance and Isothermal Titration Calorimetry
- Have a diploma and/or a master’s degree in biology, biochemistry, or biotechnology.
- Have excellent track record from their previous studies along with experience and expertise in at least one of these fields: biochemistry, protein expression, x-ray crystallography, protein biophysics. Good knowledge of chemistry is a plus.
- Fluent in English language (spoken and written/proficiency level).
- UCB in collaboration with the TUE will offer the PhD student a unique opportunity to gain world class knowledge and hands-on experience in various applications of chemical biology and drug discovery in an industrial environment.
- UCB has a strong and highly experienced structural biology and biophysics groups at Slough that can offer a broad range of support and training across multiple techniques.
- A unique aspect of working at UCB is the close collaboration of both small molecule and antibody research teams and the potential to gain added insight into the nature of protein-protein interactions. Lawson, Nature Reviews Drug Discovery 11, 519-525 (July 2012)
- The successful candidate will also participate in the network’s training activities and work placements at the laboratories of other participating academic and industrial teams.
About UCB: www.ucb.com
UCB is a global biopharmaceutical company headquartered in Brussels with a portfolio of small molecule and antibody based therapies for the treatment of severe immune-mediated diseases and CNS disorders. With over 8,000 people in approximately 40 countries, the company generated revenue of €3.8 billion in 2015. UCB has research based in Braine l’Alleud, Belgium and in Slough, UK supporting an innovative pipeline of novel therapeutics. UCB’s core products are treating patients with epilepsy, rheumatoid arthritis and Parkinson’s disease.
Researchers at our site in Slough have a strong background in structure-based drug design and are focused on the development of compounds to modulate protein-protein interactions. UCB has a track-record of working with academia and is currently collaborating with world class institutions on multiple targets in CNS, Immunology and other therapeutic areas.