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Trends Pharmacol Sci. 2010 Dec;31(12):567-74. doi: 10.1016/j.tips.2010.08.006. Epub 2010 Sep 25.

The minor binding pocket: a major player in 7TM receptor activation.

Author information

1
Laboratory for Molecular Pharmacology, Institute for Neuroscience and Pharmacology, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen, Denmark. rosenkilde@sund.ku.dk

Abstract

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-VII 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.

PMID:
20870300
DOI:
10.1016/j.tips.2010.08.006
[Indexed for MEDLINE]

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