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J. Biol. Chem., Vol. 281, Issue 25, 17337-17346, June 23, 2006

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Metal Ion Site Engineering Indicates a Global Toggle Switch Model for Seven-transmembrane Receptor Activation^*

Christian E. Elling, Thomas M. Frimurer, Lars-Ole Gerlach, Rasmus Jorgensen, Birgitte Holst, and Thue W. Schwartz¹

From the Laboratory for Molecular Pharmacology, Panum Institute, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen, Denmark and 7TM Pharma A/S, Fremtidsvej 3, DK-2970 Hørsholm, Denmark

Much evidence indicates that, during activation of seven-transmembrane (7TM) receptors, the intracellular segments of the transmembrane helices (TMs) move apart with large amplitude, rigid body movements of especially TM-VI and TM-VII. In this study, AspIII:08 (Asp¹¹³), the anchor point for monoamine binding in TM-III, was used as the starting point to engineer activating metal ion sites between the extracellular segments of the₂-adrenergic receptor. Cu(II) and Zn(II) alone and in complex with aromatic chelators acted as potent (EC₅₀ decreased to 0.5 µM) and efficacious agonists in sites constructed between positions III:08 (Asp or His), VI:16 (preferentially Cys), and/or VII:06 (preferentially Cys). In molecular models built over the backbone conformation of the inactive rhodopsin structure, the heavy atoms that coordinate the metal ion were located too far away from each other to form high affinity metal ion sites in both the bidentate and potential tridentate settings. This indicates that the residues involved 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 movement of the extracellular segments of especially TM-VI and, to some extent, TM-VII is coupled to the well established outward movement of the intracellular segments of these helices. We suggest that the pivots for these vertical seesaw movements are the highly conserved proline bends of the involved helices.

Received for publication, November 22, 2005 , and in revised form, March 22, 2006.

^* This work was supported by grants from the Novo Nordisk Foundation and the Danish Medical Research Council and by Sixth Framework Program Grant LSHB-CT-2003-503337 from the European Union. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Lab. for Molecular Pharmacology, Panum Inst., University of Copenhagen, Blegdamsvej 3, Copenhagen DK-2200, Denmark. Tel.: 45-3532-7602; Fax: 45-3532-7610; E-mail: schwartz{at}molpharm.dk.

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