Journal
TRENDS IN PHARMACOLOGICAL SCIENCES
Volume 31, Issue 12, Pages 567-574Publisher
ELSEVIER SCIENCE LONDON
DOI: 10.1016/j.tips.2010.08.006
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Funding
- Danish Council for Independent Research Medical Sciences
- NovoNordisk Foundation
- European Community [INNOCHEM: LSHB-CT-2005-518167]
- Lundbeck Foundation
- AP-Moller Foundation
- Aase and Einar Danielsen Foundation
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From the deep part of the main ligand-binding crevice, a minor, often shallower pocket extends between the extracellular ends of transmembrane domains (TM)-I, II, III and VII of 7TM receptors. This minor binding pocket is defined by a highly conserved kink in TM-II that is induced by a proline residue located in one of two adjacent positions. Here we argue that this minor binding pocket is important for receptor activation. Functional coupling of the receptors seems to be mediated through the hydrogen bond network located between the intracellular segments of these TMs, with the allosteric interface between TM-II and TM-VIl being of particular significance. Importantly, the minor binding pocket, especially the proline-kink in TM-II, is involved in G protein versus arrestin pathway-biased signaling, for example in the angiotensin AT1 system. Consequently, this pocket could be specifically targeted in the development of functionally biased drugs.
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