Ligand binding and micro-switches in 7TM receptor structures

Research output: Contribution to journalJournal articleResearchpeer-review

Rie Nygaard, Thomas M Frimurer, Birgitte Holst, Mette M Rosenkilde, Thue W Schwartz

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.
Original languageEnglish
JournalTIPS - Trends in Pharmacological Sciences
Volume30
Issue number5
Pages (from-to)249-59
Number of pages10
ISSN0165-6147
DOIs
Publication statusPublished - 2009

Bibliographical 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

ID: 14304642