ABSTRACT Partly due to lack of detailed knowledge of the molecular recognition of ligands the structural basis for partial versus full agonism is not known. In the  2 -adrenergic receptor the agonist binding site has previously been structurally and functionally exchanged with an activating metal-ion site located between AspIII:08 -or a His residue introduced at this position in transmembrane domain (TM)-III-and a Cys residue substituted for AsnVII:06 in TM-VII. Here, this interhelical, bidentate metal-ion site is without loss of Zn 2ϩ affinity transferred to the tachykinin NK 1 receptor. In contrast to the similarly mutated  2 -adrenergic receptor, signal transduction-i.e., inositol phosphate turnover-could be stimulated by both Zn 2ϩ and by the natural agonist, Substance P in the mutated NK 1 receptor. The metal-ion acted as a 25% partial agonist through binding to the bidentate zinc switch located exactly one helical turn below the two previously identified interaction points for Substance P in, respectively, TM-III and -VII. The metal-ion chelator, phenantroline, which in the  2 -adrenergic receptor increased both the potency and the agonistic efficacy of Zn 2ϩ or Cu 2ϩ in complex with the chelator, also bound to the metal-ion site-engineered NK 1 receptor, but here the metal-ion chelator complex instead acted as a pure antagonist. It is concluded that signaling of even distantly related rhodopsin-like 7TM receptors can be activated through Zn 2ϩ coordination between metal-ion binding residues located at positions III:08 and VII:06. It is suggested that only partial agonism is obtained through this simple well defined metal-ion coordination due to lack of proper interactions with residues also in TM-VI. Mutational mapping and cross-linking experiments have provided much information concerning binding pockets for ligands in 7-transmembrane (TM) receptor
