PT  - JOURNAL ARTICLE
AU  - Birgitte Holst
AU  - Christian E. Elling
AU  - Thue W. Schwartz
TI  - Partial Agonism through a Zinc-Ion Switch Constructed between Transmembrane Domains III and VII in the Tachykinin NK<sub>1</sub> Receptor
AID  - 10.1124/mol.58.2.263
DP  - 2000 Aug 01
TA  - Molecular Pharmacology
PG  - 263--270
VI  - 58
IP  - 2
4099  - http://molpharm.aspetjournals.org/content/58/2/263.short
4100  - http://molpharm.aspetjournals.org/content/58/2/263.full
SO  - Mol Pharmacol2000 Aug 01; 58
AB  - 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 β2-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 Zn2+ affinity transferred to the tachykinin NK1receptor. In contrast to the similarly mutated β2-adrenergic receptor, signal transduction—i.e., inositol phosphate turnover—could 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 β2-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.