During the last couple of years our understanding of GPCR function at the molecular level has been considerably improved. The application of advanced biophysical techniques as well as the availability of high-resolution structural information has allowed insight both into conformational changes accompanying GPCR activation and the underlying molecular mechanims governing transition of the receptor between its active and inactive states. In particular, parallel studies in rhodopsin and the p2 adrenergic receptor have supported a evolutionary conserved mechanism where disruption of intramolecular interactions between TM3 and TM6 leads to a major conformational change of TM6 relative to the rest of the receptor. The next key question is obviously to understand how the associated hetrotri-meric G protein senses this evolutionary conserved conformational change. High-resolution structural information of the hetrotrimeric G proteins has been available for a while (Wall etal. 1995; Lambright etal. 1996) and now a high-resolution structure of at least the inactive state of rhodopsin is available. Nevertheless, the orientation of the G protein relative to the receptor and how the signal is transmitted from the predicted G protein coupling domain to the guanine nucleotide binding domain in the G protein a-subunit still remains rather speculative. Its clarification will await further studies including hopefully at some point a high-resolution crystal structure of the entire receptor/G protein complex.
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