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Papers In Press, published online ahead of print March 27, 2006
Department of Pharmacology, University of Copenhagen, Panum Institute, Copenhagen DDK-2200
Corresponding Author: schwartz{at}molpharm.dk
Much evidence indicates that during activation of 7TM receptors the intra-cellular segments of the trans-membrane helices (TM’s) move apart with large-amplitude, rigid-body movements of especially TM-VI and -VII. In the present study AspIII:08 (Asp113) - the anchor point for monoamine binding in TM-III - was used as the starting point for engineering of activating metal-ion sites between the extracellular segments of the
J. Biol. Chem, 10.1074/jbc.M512510200
Submitted on November 22, 2005
Accepted on March 27, 2006
Metal-ion site engineering indicating a global toggle switch model for 7TM receptor activation
2-adrenergic receptor. Cu(II) or Zn(II) alone or in complex with aromatic chelators acted as potent – EC50 down to 0.5 
M - and efficacious agonists in sites constructed between positions III:08 (Asp or His) and VI:16 (preferentially Cys) and/or VII:06 (preferentially Cys). In molecular models built over the back-bone conformation of the inactive rhodopsin structure, the heavy atoms, which coordinate the metal-ion, were however located too far away from each other to form a high affinity metal-ion sites both in the bi-dentate and the potential tri-dentate settings. This indicates that the involved residues in the main ligand-binding pocket will have to move closer to each other during receptor activation. On the basis of the distance constraints from these activating metal-ion sites, we propose a global toggle-switch mechanism for 7TM receptor activation in which inward movements of the extracellular segments of especially TM-VI and to some extend TM-VII is coupled to the well established outward movement of the intracellular segments of these helices. It is suggested that the pivots for these vertical see-saw movements are the highly conserved proline-bends of the involved helices.
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