Ligand binding and micro-switches in 7TM receptor structures

Research output: Contribution to journal › Journal article › Research › peer-review

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Ligand binding and micro-switches in 7TM receptor structures. / Nygaard, Rie; Frimurer, Thomas M; Holst, Birgitte; Rosenkilde, Mette M; Schwartz, Thue W.

In: TIPS - Trends in Pharmacological Sciences, Vol. 30, No. 5, 2009, p. 249-59.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Nygaard, R, Frimurer, TM, Holst, B, Rosenkilde, MM & Schwartz, TW 2009, 'Ligand binding and micro-switches in 7TM receptor structures', TIPS - Trends in Pharmacological Sciences, vol. 30, no. 5, pp. 249-59. https://doi.org/10.1016/j.tips.2009.02.006

APA

Nygaard, R., Frimurer, T. M., Holst, B., Rosenkilde, M. M., & Schwartz, T. W. (2009). Ligand binding and micro-switches in 7TM receptor structures. TIPS - Trends in Pharmacological Sciences, 30(5), 249-59. https://doi.org/10.1016/j.tips.2009.02.006

Vancouver

Nygaard R, Frimurer TM, Holst B, Rosenkilde MM, Schwartz TW. Ligand binding and micro-switches in 7TM receptor structures. TIPS - Trends in Pharmacological Sciences. 2009;30(5):249-59. https://doi.org/10.1016/j.tips.2009.02.006

Author

Nygaard, Rie ; Frimurer, Thomas M ; Holst, Birgitte ; Rosenkilde, Mette M ; Schwartz, Thue W. / Ligand binding and micro-switches in 7TM receptor structures. In: TIPS - Trends in Pharmacological Sciences. 2009 ; Vol. 30, No. 5. pp. 249-59.

Bibtex

@article{1fd5d4909d2d11debc73000ea68e967b,
title = "Ligand binding and micro-switches in 7TM receptor structures",
abstract = "The past couple of years have seen several novel X-ray structures of 7 transmembrane (7TM) receptors in complex with antagonists and even with a peptide fragment of a G protein. These structures demonstrate that the main ligand-binding pocket in 7TM receptors is like a funnel with a partial 'lid' in which extracellular loop 2b, in particular, functions as a gating element. Small-molecule antagonists and inverse agonists bind in very different modes: some very deeply and others more superficially, even reaching out above the transmembranes. Several highly conserved residues seem to function as micro-switches of which ArgIII:26 (Arg3.50) in its active conformation interacts directly with the G protein. These micro-switches together with a hydrogen-bond network between conserved polar residues and structural water molecules are proposed to constitute an extended allosteric interface between the domains (i.e. especially TM-VI), which performs the large, global toggle switch movements connecting ligand binding with intracellular signaling.",
author = "Rie Nygaard and Frimurer, {Thomas M} and Birgitte Holst and Rosenkilde, {Mette M} and Schwartz, {Thue W}",
note = "Keywords: Allosteric Regulation; Binding Sites; Drug Agonism; Drug Antagonism; Ligands; Models, Molecular; Molecular Conformation; Molecular Structure; Protein Interaction Domains and Motifs; Receptors, G-Protein-Coupled",
year = "2009",
doi = "10.1016/j.tips.2009.02.006",
language = "English",
volume = "30",
pages = "249--59",
journal = "Trends in Pharmacological Sciences",
issn = "0165-6147",
publisher = "Elsevier Ltd. * Trends Journals",
number = "5",

}

RIS

TY - JOUR

T1 - Ligand binding and micro-switches in 7TM receptor structures

AU - Nygaard, Rie

AU - Frimurer, Thomas M

AU - Holst, Birgitte

AU - Rosenkilde, Mette M

AU - Schwartz, Thue W

N1 - Keywords: Allosteric Regulation; Binding Sites; Drug Agonism; Drug Antagonism; Ligands; Models, Molecular; Molecular Conformation; Molecular Structure; Protein Interaction Domains and Motifs; Receptors, G-Protein-Coupled

PY - 2009

Y1 - 2009

N2 - The past couple of years have seen several novel X-ray structures of 7 transmembrane (7TM) receptors in complex with antagonists and even with a peptide fragment of a G protein. These structures demonstrate that the main ligand-binding pocket in 7TM receptors is like a funnel with a partial 'lid' in which extracellular loop 2b, in particular, functions as a gating element. Small-molecule antagonists and inverse agonists bind in very different modes: some very deeply and others more superficially, even reaching out above the transmembranes. Several highly conserved residues seem to function as micro-switches of which ArgIII:26 (Arg3.50) in its active conformation interacts directly with the G protein. These micro-switches together with a hydrogen-bond network between conserved polar residues and structural water molecules are proposed to constitute an extended allosteric interface between the domains (i.e. especially TM-VI), which performs the large, global toggle switch movements connecting ligand binding with intracellular signaling.

AB - The past couple of years have seen several novel X-ray structures of 7 transmembrane (7TM) receptors in complex with antagonists and even with a peptide fragment of a G protein. These structures demonstrate that the main ligand-binding pocket in 7TM receptors is like a funnel with a partial 'lid' in which extracellular loop 2b, in particular, functions as a gating element. Small-molecule antagonists and inverse agonists bind in very different modes: some very deeply and others more superficially, even reaching out above the transmembranes. Several highly conserved residues seem to function as micro-switches of which ArgIII:26 (Arg3.50) in its active conformation interacts directly with the G protein. These micro-switches together with a hydrogen-bond network between conserved polar residues and structural water molecules are proposed to constitute an extended allosteric interface between the domains (i.e. especially TM-VI), which performs the large, global toggle switch movements connecting ligand binding with intracellular signaling.

U2 - 10.1016/j.tips.2009.02.006

DO - 10.1016/j.tips.2009.02.006

M3 - Journal article

C2 - 19375807

VL - 30

SP - 249

EP - 259

JO - Trends in Pharmacological Sciences

JF - Trends in Pharmacological Sciences

SN - 0165-6147

IS - 5

ER -

ID: 14304642