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

@article{citeulike:679504, abstract = {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.}, address = {Laboratory for Molecular Pharmacology, The Panum Institute, University of Copenhagen, and 7TM Pharma A/S, Hørsholm, Denmark. schwartz@molpharm.dk}, author = {Schwartz, T. W. and Frimurer, T. M. and Holst, B. and Rosenkilde, M. M. and Elling, C. E. }, citeulike-article-id = {679504}, doi = {http://dx.doi.org/10.1146/annurev.pharmtox.46.120604.141218}, issn = {0362-1642}, journal = {Annu Rev Pharmacol Toxicol}, keywords = {activation, gpcr, helix, modeling, switch, toggle}, pages = {481--519}, posted-at = {2006-06-01 14:31:34}, priority = {0}, title = {Molecular mechanism of 7TM receptor activation--a global toggle switch model.}, url = {http://dx.doi.org/10.1146/annurev.pharmtox.46.120604.141218}, volume = {46}, year = {2006} }

TY - JOUR ID - citeulike:679504 L3 - citeulike-article-id:679504 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. JF - Annu Rev Pharmacol Toxicol SN - 0362-1642 AD - Laboratory for Molecular Pharmacology, The Panum Institute, University of Copenhagen, and 7TM Pharma A/S, Hørsholm, Denmark. schwartz@molpharm.dk EP - 519 TI - Molecular mechanism of 7TM receptor activation--a global toggle switch model. VL - 46 SP - 481 KW - activation KW - gpcr KW - helix KW - modeling KW - switch KW - toggle AU - Schwartz, TW AU - Frimurer, TM AU - Holst, B AU - Rosenkilde, MM AU - Elling, CE PY - 2006/// UR - http://dx.doi.org/10.1146/annurev.pharmtox.46.120604.141218 ER -