ERC Proof of Concept Grant: MMC

Membrane Micro-Compartments

Investigator: Martin Beck
Project Period: 2024–2025

Objective:
More than two-thirds of all described drug targets are membrane proteins, but only for a small fraction of these hydrophobic proteins the structure is currently known. Membrane proteins are inherently challenging to produce and analyze. Consequently, in pre-clinical investigations their mechanism and drug interactions are often only derived from purified truncated parts of these proteins, taken out of their native biological context. Lacking the effects of surrounding membrane components, conclusions on drug mechanisms are
indecisive. Recent advances in in situ structure determination techniques, i.e. analysis directly within the cellular environment, now have the power to overcome the limitations of classical reconstituted approaches. Complementary, we have developed an inducible membrane micro-compartment (MMC) system in yeast, which allows for the enrichment of any membrane protein inside MMCs. Our system may thus facilitate in situ structural analysis of membrane protein drug targets directly in cells and has large potential for the production of native membrane proteins - an essential prerequisite for the study of membrane protein function and drug interactions. Within the scope of our proposal, we will further develop our system and transfer it into a pharmaceutically relevant human cellbased system. Furthermore, we aim to achieve proof-of-concept (PoC) and assess our MMCs with clinically relevant membrane
proteins for their suitability to solve 3D structures in complex with clinical drugs, as well as suitability of MMCs for the production of native membrane vesicles enriched for defined membrane protein targets. We are convinced that our approach will have a transformative impact on how drug - membrane protein interactions can be studied, and could be exploited for drug development in the pharmaceutical industry. In the course of the MMC project, we will establish a plan for transforming our system into a business model and commercializing our technology. more

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