The key problem to be addressed in the current proposal is the study of some of the most pivotal growth receptors of the cell at high resolution in their cellular context. Members of the Epidermal Growth Factors Receptor family (EGFRs) influence cell growth and proliferation and are critical in all phases of tumor progression. Therefore, they have been the target of many therapeutic interventions, such as therapeutic antibodies, kinase inhibitors but also many novel experimental therapies aiming to inhibit their function to control tumor growth. Despite their enormous importance, the exact structure of these receptors within the natural cell membrane, their detailed interaction with other cellular factors and their exact interaction with therapeutic substances is not understood. The impact of having a precise structural understanding as well as their dynamics of interaction can hardly be overestimated. Moreover, the technical developments emerging out of this project serve as a blueprint to study other important cell receptors in an analogous manner.
The importance of this work for society lies in the fact that an understanding of the structure and dynamics of these receptors in their natural environment holds the key to develop better drugs, most importantly in the field of anti-cancer drugs. Only if we understand how the natural receptors act and interact can we design optimal molecules to prevent this with high specificity and thus few side effects for the patient. Therefore, the present work will have fundamental consequences for developing new anti-cancer medicines.
The overall objectives are to use defined membrane vesicles and whole cells, and employ 3D structure analysis by cryo-electron microscopy, especially tomography, greatly enhanced by novel image processing approaches, mass spectroscopy definitions of receptor modifications and interaction partners, as well as advanced protein engineering to identify, orient and freeze receptors for this method development. This collaborative project addresses the properties of such important receptors across a wide range of complexity and dimensions, in the cellular environment, through their high-resolution structures and changes during receptor recycling.
Moreover, the technology that has been developed will be generally applicable and may thus help to contribute to a paradigm change for structural biology, enabling atomic resolution description of receptors in their cellular environment.
