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Crystallisation and functional analysis of rhodopsin bound to its effector arrestin

Final Activity Report Summary - ARRESTED RHODOPSIN (Crystallisation and functional analysis of rhodopsin bound to its effector arrestin)

The role of G protein-coupled receptors (GPCRs) in humans is of great medical importance. Since these proteins can interact with the environment both inside and outside the cell, they act as a receptor of chemical signals that activate a variety of cellular reactions. Many medical drugs mimic these signals to influence body reactions like heart beat, digestion or neuronal activity.

The development of future drugs is facilitated by a detailed understanding of how GPCRs transfer their signal across the cellular membrane. A crucial key for our understanding is the availability of high-resolution structures illuminating all steps of the GPCR reaction cycle.

Rhodopsin, the dim light sensor of the human eye, gives us the unique opportunity to follow these reaction cycles. Consequently, rhodopsin is the only GPCR for which structures of several intermediates were already determined, much of which was done in the laboratory which hosted the fellow.

The ‘Marie Curie’ funding allowed for significant progress towards visualising the fully active conformation of rhodopsin. To do this, human cells were altered to produce genetically modified rhodopsin in a stable form, i.e. a form that could be used more easily by the techniques applied to determine the structure of proteins. The structure of this stabilised rhodopsin could therefore be solved, and this was the first time that this was possible for a GPCR produced by recombinant technology. Several additional alterations to the receptor were also created to allow for the stable binding of arrestin and G protein, proteins known to arrest GPCRs in their active conformation.

Our next challenge would be to determine the structure of such an activated receptor complex so as to find out how signals were transmitted. Our knowledge of these receptor structures would allow us to make significant steps towards a better treatment of GPRC-related illnesses.