Gating function of isoleucine-116 in TM-3 (position III:16/3.40) for the activity state of the CC-chemokine receptor 5 (CCR5)

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Gating function of isoleucine-116 in TM-3 (position III:16/3.40) for the activity state of the CC-chemokine receptor 5 (CCR5). / Steen, A; Sparre-Ulrich, A H; Thiele, Stefanie; Guo, D; Frimurer, T M; Rosenkilde, M M.

I: British Journal of Pharmacology, Bind 171, Nr. 6, 03.2014, s. 1566-79.

Publikation: Bidrag til tidsskriftTidsskriftartikelfagfællebedømt

Harvard

Steen, A, Sparre-Ulrich, AH, Thiele, S, Guo, D, Frimurer, TM & Rosenkilde, MM 2014, 'Gating function of isoleucine-116 in TM-3 (position III:16/3.40) for the activity state of the CC-chemokine receptor 5 (CCR5)', British Journal of Pharmacology, bind 171, nr. 6, s. 1566-79. https://doi.org/10.1111/bph.12553

APA

Steen, A., Sparre-Ulrich, A. H., Thiele, S., Guo, D., Frimurer, T. M., & Rosenkilde, M. M. (2014). Gating function of isoleucine-116 in TM-3 (position III:16/3.40) for the activity state of the CC-chemokine receptor 5 (CCR5). British Journal of Pharmacology, 171(6), 1566-79. https://doi.org/10.1111/bph.12553

Vancouver

Steen A, Sparre-Ulrich AH, Thiele S, Guo D, Frimurer TM, Rosenkilde MM. Gating function of isoleucine-116 in TM-3 (position III:16/3.40) for the activity state of the CC-chemokine receptor 5 (CCR5). British Journal of Pharmacology. 2014 mar.;171(6):1566-79. https://doi.org/10.1111/bph.12553

Author

Steen, A ; Sparre-Ulrich, A H ; Thiele, Stefanie ; Guo, D ; Frimurer, T M ; Rosenkilde, M M. / Gating function of isoleucine-116 in TM-3 (position III:16/3.40) for the activity state of the CC-chemokine receptor 5 (CCR5). I: British Journal of Pharmacology. 2014 ; Bind 171, Nr. 6. s. 1566-79.

Bibtex

@article{ebf1680dacfc4f009b6a1efc1e947128,
title = "Gating function of isoleucine-116 in TM-3 (position III:16/3.40) for the activity state of the CC-chemokine receptor 5 (CCR5)",
abstract = "BACKGROUND AND PURPOSE: A conserved amino acid within a protein family indicates a significance of the residue. In the centre of transmembrane helix (TM)-5, position V:13/5.47, an aromatic amino acid is conserved among class A 7TM receptors. However, in 37% of chemokine receptors - a subgroup of 7TM receptors - it is a leucine indicating an altered function. Here, we describe the significance of this position and its possible interaction with TM-3 for CCR5 activity.EXPERIMENTAL APPROACH: The effects of [L203F]-CCR5 in TM-5 (position V:13/5.47), [I116A]-CCR5 in TM-3 (III:16/3.40) and [L203F;G286F]-CCR5 (V:13/5.47;VII:09/7.42) were determined in G-protein- and β-arrestin-coupled signalling. Computational modelling monitored changes in amino acid conformation.KEY RESULTS: [L203F]-CCR5 increased the basal level of G-protein coupling (20-70% of Emax ) and β-arrestin recruitment (50% of Emax ) with a threefold increase in agonist potency. In silico, [I116A]-CCR5 switched χ1-angle in [L203F]-CCR5. Furthermore, [I116A]-CCR5 was constitutively active to a similar degree as [L203F]-CCR5. Tyr(244) in TM-6 (VI:09/6.44) moved towards TM-5 in silico, consistent with its previously shown function for CCR5 activation. On [L203F;G286F]-CCR5 the antagonist aplaviroc was converted to a superagonist.CONCLUSIONS AND IMPLICATIONS: The results imply that an aromatic amino acid in the centre of TM-5 controls the level of receptor activity. Furthermore, Ile(116) acts as a gate for the movement of Tyr(244) towards TM-5 in the active state, a mechanism proposed previously for the β2 -adrenoceptor. The results provide an understanding of chemokine receptor function and thereby information for the development of biased and non-biased antagonists and inverse agonists.",
keywords = "Amino Acid Sequence, Animals, COS Cells, Cercopithecus aethiops, Enzyme-Linked Immunosorbent Assay, Humans, Ion Channel Gating, Isoleucine, Molecular Sequence Data, Receptors, CCR5, Sequence Homology, Amino Acid",
author = "A Steen and Sparre-Ulrich, {A H} and Stefanie Thiele and D Guo and Frimurer, {T M} and Rosenkilde, {M M}",
note = "{\textcopyright} 2013 The British Pharmacological Society.",
year = "2014",
month = mar,
doi = "10.1111/bph.12553",
language = "English",
volume = "171",
pages = "1566--79",
journal = "British Journal of Pharmacology",
issn = "0007-1188",
publisher = "Wiley",
number = "6",

}

RIS

TY - JOUR

T1 - Gating function of isoleucine-116 in TM-3 (position III:16/3.40) for the activity state of the CC-chemokine receptor 5 (CCR5)

AU - Steen, A

AU - Sparre-Ulrich, A H

AU - Thiele, Stefanie

AU - Guo, D

AU - Frimurer, T M

AU - Rosenkilde, M M

N1 - © 2013 The British Pharmacological Society.

PY - 2014/3

Y1 - 2014/3

N2 - BACKGROUND AND PURPOSE: A conserved amino acid within a protein family indicates a significance of the residue. In the centre of transmembrane helix (TM)-5, position V:13/5.47, an aromatic amino acid is conserved among class A 7TM receptors. However, in 37% of chemokine receptors - a subgroup of 7TM receptors - it is a leucine indicating an altered function. Here, we describe the significance of this position and its possible interaction with TM-3 for CCR5 activity.EXPERIMENTAL APPROACH: The effects of [L203F]-CCR5 in TM-5 (position V:13/5.47), [I116A]-CCR5 in TM-3 (III:16/3.40) and [L203F;G286F]-CCR5 (V:13/5.47;VII:09/7.42) were determined in G-protein- and β-arrestin-coupled signalling. Computational modelling monitored changes in amino acid conformation.KEY RESULTS: [L203F]-CCR5 increased the basal level of G-protein coupling (20-70% of Emax ) and β-arrestin recruitment (50% of Emax ) with a threefold increase in agonist potency. In silico, [I116A]-CCR5 switched χ1-angle in [L203F]-CCR5. Furthermore, [I116A]-CCR5 was constitutively active to a similar degree as [L203F]-CCR5. Tyr(244) in TM-6 (VI:09/6.44) moved towards TM-5 in silico, consistent with its previously shown function for CCR5 activation. On [L203F;G286F]-CCR5 the antagonist aplaviroc was converted to a superagonist.CONCLUSIONS AND IMPLICATIONS: The results imply that an aromatic amino acid in the centre of TM-5 controls the level of receptor activity. Furthermore, Ile(116) acts as a gate for the movement of Tyr(244) towards TM-5 in the active state, a mechanism proposed previously for the β2 -adrenoceptor. The results provide an understanding of chemokine receptor function and thereby information for the development of biased and non-biased antagonists and inverse agonists.

AB - BACKGROUND AND PURPOSE: A conserved amino acid within a protein family indicates a significance of the residue. In the centre of transmembrane helix (TM)-5, position V:13/5.47, an aromatic amino acid is conserved among class A 7TM receptors. However, in 37% of chemokine receptors - a subgroup of 7TM receptors - it is a leucine indicating an altered function. Here, we describe the significance of this position and its possible interaction with TM-3 for CCR5 activity.EXPERIMENTAL APPROACH: The effects of [L203F]-CCR5 in TM-5 (position V:13/5.47), [I116A]-CCR5 in TM-3 (III:16/3.40) and [L203F;G286F]-CCR5 (V:13/5.47;VII:09/7.42) were determined in G-protein- and β-arrestin-coupled signalling. Computational modelling monitored changes in amino acid conformation.KEY RESULTS: [L203F]-CCR5 increased the basal level of G-protein coupling (20-70% of Emax ) and β-arrestin recruitment (50% of Emax ) with a threefold increase in agonist potency. In silico, [I116A]-CCR5 switched χ1-angle in [L203F]-CCR5. Furthermore, [I116A]-CCR5 was constitutively active to a similar degree as [L203F]-CCR5. Tyr(244) in TM-6 (VI:09/6.44) moved towards TM-5 in silico, consistent with its previously shown function for CCR5 activation. On [L203F;G286F]-CCR5 the antagonist aplaviroc was converted to a superagonist.CONCLUSIONS AND IMPLICATIONS: The results imply that an aromatic amino acid in the centre of TM-5 controls the level of receptor activity. Furthermore, Ile(116) acts as a gate for the movement of Tyr(244) towards TM-5 in the active state, a mechanism proposed previously for the β2 -adrenoceptor. The results provide an understanding of chemokine receptor function and thereby information for the development of biased and non-biased antagonists and inverse agonists.

KW - Amino Acid Sequence

KW - Animals

KW - COS Cells

KW - Cercopithecus aethiops

KW - Enzyme-Linked Immunosorbent Assay

KW - Humans

KW - Ion Channel Gating

KW - Isoleucine

KW - Molecular Sequence Data

KW - Receptors, CCR5

KW - Sequence Homology, Amino Acid

U2 - 10.1111/bph.12553

DO - 10.1111/bph.12553

M3 - Journal article

C2 - 24328926

VL - 171

SP - 1566

EP - 1579

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

IS - 6

ER -

ID: 137818242