Hartmut Michel

Membrane Proteins as Target-Structure in Agriculture and Medicine


Abstract

Membrane proteins constitute the majority of the drug targets in medicine. Also, many pesticides, especially herbicides and fungicides act by binding to membrane proteins. Historically, drug discovery and drug development have relied on accidental observations and traditional, herbal medicine. A more rational way of drug development has been introduced when hormones, neurotransmitters and enzymatic substrates where identified and their chemical structures were determined, and chemists were able to synthesize structurally related analogues that acted as agonists or antagonists. This phase had to come to an end, and it has been replaced by high-throughput screening of huge libraries of chemical compounds using identified targets. High-throughput screening did not live up to the general expectations, and the big hope now resides in structure-based drug development. For this method the precise atomic structure of the drug target is required, before rational drug design or virtual screening can be employed to develop new and specific drugs. Membrane proteins will continue to constitute the majority of drug targets, because it is the membrane level where specificity in signal transduction is achieved.
Structure-based drug development requires knowledge of the structures of the drug target. Structural knowledge of membrane proteins is difficult to generate because membrane proteins are difficult to handle. The recent successes of the author’s lab will be described, as well as the attempts towards getting the structures of the so-called G-protein coupled receptors, which constitute the medically and economically most important receptor class. Here the bottle neck resides in the production of sufficient amounts of homogeneous and stable receptors for structural studies.


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