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

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.

journal_name

Trends Pharmacol Sci

authors

Rosenkilde MM,Benned-Jensen T,Frimurer TM,Schwartz TW

doi

10.1016/j.tips.2010.08.006

subject

Has Abstract

pub_date

2010-12-01 00:00:00

pages

567-74

issue

12

eissn

0165-6147

issn

1873-3735

pii

S0165-6147(10)00152-5

journal_volume

31

pub_type

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