Ligand binding and micro-switches in 7TM receptor structures.
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.
Laboratory for Molecular Pharmacology, Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, DK-2200, Denmark.
Rie
R
Nygaard
Thomas M
TM
Frimurer
Birgitte
B
Holst
Mette M
MM
Rosenkilde
Thue W
TW
Schwartz
D000494:Allosteric Regulation; D001665:Binding Sites; D054313:Drug Agonism; D004336:Drug Antagonism; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D054730:Protein Interaction Domains and Motifs; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry*
D008024:Ligands; D043562:Receptors, G-Protein-Coupled; C450520:seven-transmembrane G-protein-coupled receptor