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Common drugs initiate a molecular pas de quatre at the surface of the cell membrane
Date:7/26/2011

ic G protein (Gs) to fall apart in two pieces (G-alpha-S and G-beta-gamma). One piece (G-alpha-S) transmits the adrenaline signal to an effector enzyme; the other piece (G-beta-gamma) transmits the signal to an effector ion channel.

Although the receptor beta-2AR been discovered 20 years ago, the exact mechanism of its function remained unknown, impeding improvements of the drugs that act on this receptor. To explain the function of this receptor, it was important to catch the signaling complex in the act, a dance in two parts featuring four key players: the hormone (adrenaline or noradrenaline), the receptor and the G protein that is built from G-alpha-S and G beta-gamma.

Now, 20 year later, this is exactly what the researchers Stanford University, University of Wisconsin and VIB-Vrije Universiteit Brussel have accomplished. They produced two key freeze-frame pictures of this dance. In January 2011, they produced the first images of an active receptor, coupled to a drug-like molecule that acts like the hormone. In a follow-up article in Nature, they now present the poignant moment in the ballet the four-partner embrace that includes the hormone, the receptor, G-alpha-S and G-beta-gamma. These findings provide the very first three dimensional insights in transmembrane signaling trough GPCRs, a molecular process that is considered to be one of the most fascinating problems in biology. The discovery is important because the interactions between the GPCR and G-alpha-beta-gamma are pharmacologically relevant and unlock the secrets of functional selectivity, the ability of different drugs to coax distinct downstream effects from a single kind of receptor.

Obtaining a 3D image of the Hormone:GPCR:G-alpha-beta-gamma complex proved to be very complicated. The large and membrane embedded complex is unstable, difficult to prepare and the components are difficult to express and purify. Jan Steyaert and Els Pardon in Brussels produced a Xaperone, that
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Contact: Joris Gansemans
info@vib.be
32-924-46611
VIB (the Flanders Institute for Biotechnology)
Source:Eurekalert

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