TY - JOUR

T1 - Molecular mechanism of 7TM receptor activation--a global toggle switch model

AU - Schwartz, Thue W

AU - Frimurer, Thomas M

AU - Holst, Birgitte

AU - Rosenkilde, Mette M

AU - Elling, Christian E

N1 - Keywords: Animals; Cytoplasm; Humans; Models, Molecular; Molecular Conformation; Receptor, Muscarinic M2; Receptors, G-Protein-Coupled

PY - 2006

Y1 - 2006

N2 - The multitude of chemically highly different agonists for 7TM receptors apparently do not share a common binding mode or active site but nevertheless act through induction of a common molecular activation mechanism. A global toggle switch model is proposed for this activation mechanism to reconcile the accumulated biophysical data supporting an outward rigid-body movement of the intracellular segments, as well as the recent data derived from activating metal ion sites and tethered ligands, which suggests an opposite, inward movement of the extracellular segments of the transmembrane helices. According to this model, a vertical see-saw movement of TM-VI-and to some degree TM-VII-around a pivot corresponding to the highly conserved prolines will occur during receptor activation, which may involve the outer segment of TM-V in an as yet unclear fashion. Small-molecule agonists can stabilize such a proposed active conformation, where the extracellular segments of TM-VI and -VII are bent inward toward TM-III, by acting as molecular glue deep in the main ligand-binding pocket between the helices, whereas larger agonists, peptides, and proteins can stabilize a similar active conformation by acting as Velcro at the extracellular ends of the helices and the connecting loops.

AB - The multitude of chemically highly different agonists for 7TM receptors apparently do not share a common binding mode or active site but nevertheless act through induction of a common molecular activation mechanism. A global toggle switch model is proposed for this activation mechanism to reconcile the accumulated biophysical data supporting an outward rigid-body movement of the intracellular segments, as well as the recent data derived from activating metal ion sites and tethered ligands, which suggests an opposite, inward movement of the extracellular segments of the transmembrane helices. According to this model, a vertical see-saw movement of TM-VI-and to some degree TM-VII-around a pivot corresponding to the highly conserved prolines will occur during receptor activation, which may involve the outer segment of TM-V in an as yet unclear fashion. Small-molecule agonists can stabilize such a proposed active conformation, where the extracellular segments of TM-VI and -VII are bent inward toward TM-III, by acting as molecular glue deep in the main ligand-binding pocket between the helices, whereas larger agonists, peptides, and proteins can stabilize a similar active conformation by acting as Velcro at the extracellular ends of the helices and the connecting loops.

U2 - 10.1146/annurev.pharmtox.46.120604.141218

DO - 10.1146/annurev.pharmtox.46.120604.141218

M3 - Journal article

C2 - 16402913

VL - 46

SP - 481

EP - 519

JO - Annual Review of Pharmacology and Toxicology

JF - Annual Review of Pharmacology and Toxicology

SN - 0362-1642

ER -