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Vol. 58, Issue 2, 263-270, August 2000
Laboratory for Molecular Pharmacology, Department of Pharmacology,
The Panum Institute, Copenhagen University, Copenhagen, Denmark
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)-IIIand a Cys residue substituted for AsnVII:06 in TM-VII. Here,
this interhelical, bidentate metal-ion site is without loss of
Zn2+ affinity transferred to the tachykinin NK1
receptor. In contrast to the similarly mutated
2-adrenergic receptor, signal transductioni.e., inositol phosphate turnovercould be stimulated by both
Zn2+ and by the natural agonist, Substance P in the mutated
NK1 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
Zn2+ or Cu2+ in complex with the chelator, also
bound to the metal-ion site-engineered NK1 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 Zn2+ 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.
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