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J. Biol. Chem., Vol. 278, Issue 1, 352-356, January 3, 2003

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Identification of an Allosteric Binding Site for Zn²⁺ on the ₂ Adrenergic Receptor^*

Gayathri Swaminath, Tae Weon Lee, and Brian Kobilka

From the Department of Molecular and Cellular Physiology, Howard Hughes Medical Institute, Stanford Medical Center, Stanford, Palo Alto, California 94305

The activity of G protein-coupled receptors (GPCRs) can be modulated by a diverse spectrum of drugs ranging from full agonists to partial agonists, antagonists, and inverse agonists. The vast majority of these ligands compete with native ligands for binding to orthosteric binding sites. Allosteric ligands have also been described for a number of GPCRs. However, little is known about the mechanism by which these ligands modulate the affinity of receptors for orthosteric ligands. We have previously reported that Zn(II) acts as a positive allosteric modulator of the ₂-adrenergic receptor (₂AR). To identify the Zn²⁺ binding site responsible for the enhancement of agonist affinity in the ₂AR, we mutated histidines located in hydrophilic sequences bridging the seven transmembrane domains. Mutation of His-269 abolished the effect of Zn²⁺ on agonist affinity. Mutations of other histidines had no effect on agonist affinity. Further mutagenesis of residues adjacent to His-269 demonstrated that Cys-265 and Glu-225 are also required to achieve the full allosteric effect of Zn²⁺ on agonist binding. Our results suggest that bridging of the cytoplasmic extensions of TM5 and TM6 by Zn²⁺ facilitates agonist binding. These results are in agreement with recent biophysical studies demonstrating that agonist binding leads to movement of TM6 relative to TM5.

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