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J. Biol. Chem., Vol. 275, Issue 29, 21939-21945, July 21, 2000

This Article Full Text Full Text (PDF) All Versions of this Article: 275/29/21939    most recent M002864200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Meng, F. Articles by Akil, H. Search for Related Content PubMed PubMed Citation Articles by Meng, F. Articles by Akil, H. Social Bookmarking                      What's this?

Switching Agonist/Antagonist Properties of Opiate Alkaloids at the  Opioid Receptor Using Mutations Based on the Structure of the Orphanin FQ Receptor^*

Fan Meng, Qiang Wei, Mary T. Hoversten, Larry P. Taylor, and Huda Akil

From the Mental Health Research Institute, University of Michigan, Ann Arbor, Michigan 48109

In an earlier study, we have demonstrated that by mutating five amino acid residues to those conserved in the opioid receptors, the OFQ receptor could be converted to a functional receptor that bound many opioid alkaloids with nanomolar affinities. Surprisingly, when the reciprocal mutations, Lys-214  Ala (TM5), Ile-277  Val/His-278  Gln/Ile-279  Val (TM6), and Ile-304  Thr (TM7), are introduced in the  receptor, neither the individual mutations nor their various combinations significantly reduce the binding affinities of opioid alkaloids tested. However, these mutations cause profound alterations in the functional characteristics of the mutant receptors as measured in guanosine 5'-3-O-(thio)triphosphate binding assays. Some agonists become antagonists at some constructs as they lose their ability to activate them. Some alkaloid antagonists are transformed into agonists at other constructs, but their agonistic effects can still be blocked by the peptide antagonist TIPP. Even the  inverse agonist 7-benzylidenenaltrexone becomes an agonist at the mutant containing both the Ile-277  Val/His-278  Gln/Ile-279  Val and Ile-304  Thr mutations. Thus, although the mutated residues are thought to be part of the binding pocket, they are critically involved in the control of the  receptor activation process. These findings shed light on some of the structural bases of ligand efficacy. They are also compatible with the hypothesis that a ligand may achieve high affinity binding in several different ways, each having different effects on receptor activation.

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				N. A. Martin, M. B. Ruckle, S. L. VanHoof, and P. L. Prather Agonist, Antagonist, and Inverse Agonist Characteristics of TIPP (H-Tyr-Tic-Phe-Phe-OH), a Selective delta -Opioid Receptor Ligand J. Pharmacol. Exp. Ther., May 1, 2002; 301(2): 661 - 671. [Abstract] [Full Text] [PDF]

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