Ligand binding and micro-switches in 7TM receptor structures
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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
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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