Ligand binding and micro-switches in 7TM receptor structures

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

SN - 0165-6147

VL - 30

SP - 249

EP - 259

JO - Trends in Pharmacological Sciences

JF - Trends in Pharmacological Sciences

IS - 5

ER -