Structural biology as an approach to decipher molecular mechanisms

We use structural biology tools to gain insights into the molecular mechanisms of cellular signal transduction, their outcomes and their regulation. It is our conviction that structural biology combined with biochemistry, biophysics and other approaches is uniquely powerful in deciphering detailed molecular mechanisms of physiological processes in cells and organisms. As main structural techniques we employ single particle cryoEM but also machine learning-based structure  prediction tools such als AlphaFold and Boltz. Where necessary we complement this with protein x-ray crystallography. Our typical workflow usually starts with the proteins-of-interests’ coding sequences and we first develop heterologous expression, purification and reconstitution protocols from there. Once we have the protein complexes or molecular assemblies of interest in hands we characterise them biochemically and biophysically to understand their behaviour. This knowledge helps us to develop optimal sample reconstitution and preparation protocols for downstream structural analysis. We subsequently supplement the obtained experimental structural data with machine-learning aided structural modelling to build an as complete as possible structural model of the assembly in question. These models are an invaluable tool to postulate mechanistic hypothesis for cell biological processes and further probe molecular mechanisms by structure-guided experiments. All of these steps are of course highly iterative.

© Schäfer

We are well versed technically and equipment-wise to perform all these steps and are in a highly supportive environment at the ZML and PLID. We are always open to discussing potential collaborations and explore novel projects together. Just get in touch!

Ongoing projects: mechanistic structural biology of insulin signalling and Diabetes research

Molecular signal transduction and its aberrations are a key lever for transitions between life, disease and death. Insulin for example is one of the critical molecules at the basis of diabetes pathology and cure. It and other growth hormones are crucially regulating cell fate decisions and can have antagonistic metabolic or mitogenic effects by activating associated signalling cascades. Our lab focuses currently on several aspects of these signalling cascades with a particular focus on insulin signalling and Diabetes research. Many critical and challenging future questions remain in this field: How are downstream signalling complexes organised by and around activated receptors? What is the structural basis for the cellular response (e.g. increase in translation initiation)? How do disease states alter the structural basis for the cellular response? How is signal transduction attenuated and modulated? 

And last but not least our overarching goal: What are novel ways to control signalling outcomes by selectively interfering with these signalling cascades to help “heal” signalling dysmorphisms and their associated disease?