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

Mette Marie Rosenkilde; Tau Benned-Jensen; Thomas M. Frimurer; Thue W. Schwartz

doi:10.1016/j.tips.2010.08.006

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

Mette Marie Rosenkilde, Tau Benned-Jensen, Thomas M. Frimurer, Thue W. Schwartz

Institut for Neurovidenskab

94 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Trends in Pharmacological Sciences
Vol/bind	31
Udgave nummer	12
Sider (fra-til)	567-574
Antal sider	8
ISSN	0165-6147
DOI	https://doi.org/10.1016/j.tips.2010.08.006
Status	Udgivet - dec. 2010

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10.1016/j.tips.2010.08.006

Citationsformater

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title = "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.",

keywords = "Animals, Binding Sites, Drug Delivery Systems, Humans, Ligands, Models, Molecular, Protein Structure, Quaternary, Receptors, G-Protein-Coupled, Signal Transduction",

author = "Rosenkilde, {Mette Marie} and Tau Benned-Jensen and Frimurer, {Thomas M.} and Schwartz, {Thue W.}",

year = "2010",

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doi = "10.1016/j.tips.2010.08.006",

language = "English",

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T1 - The minor binding pocket: a major player in 7TM receptor activation

AU - Rosenkilde, Mette Marie

AU - Benned-Jensen, Tau

AU - Frimurer, Thomas M.

AU - Schwartz, Thue W.

PY - 2010/12

Y1 - 2010/12

N2 - 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.

AB - 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.

KW - Animals

KW - Binding Sites

KW - Drug Delivery Systems

KW - Humans

KW - Ligands

KW - Models, Molecular

KW - Protein Structure, Quaternary

KW - Receptors, G-Protein-Coupled

KW - Signal Transduction

U2 - 10.1016/j.tips.2010.08.006

DO - 10.1016/j.tips.2010.08.006

M3 - Journal article

C2 - 20870300

SN - 0165-6147

VL - 31

SP - 567

EP - 574

JO - Trends in Pharmacological Sciences

JF - Trends in Pharmacological Sciences

IS - 12

ER -

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

Abstract

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