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J. Biol. Chem., Vol. 278, Issue 36, 34451-34457, September 5, 2003

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Allosteric ₁-Adrenoreceptor Antagonism by the Conopeptide -TIA^*

Iain A. Sharpe  , Linda Thomas , Marion Loughnan , Leonid Motin , Elka Palant ¶, Daniel E. Croker ¶, Dianne Alewood ¶, Songhai Chen ||, Robert M. Graham ||, Paul F. Alewood , David J. Adams  and Richard J. Lewis   **

From the Institute for Molecular Bioscience and the School of Biomedical Sciences, The University of Queensland, St. Lucia 4072, Queensland, Australia, ^¶Xenome Ltd., 50 Meiers Road, Indooroopilly 4068, Queensland, Australia, and the ^||Molecular Cardiology Unit, Victor Chang Cardiac Research Institute, Darlinghurst 2010, New South Wales, Australia

A peptide contained in the venom of the predatory marine snail Conus tulipa, -TIA, has previously been shown to possess ₁-adrenoreceptor antagonist activity. Here, we further characterize its pharmacological activity as well as its structure-activity relationships. In the isolated rat vas deferens, -TIA inhibited ₁-adrenoreceptor-mediated increases in cytosolic Ca²⁺ concentration that were triggered by norepinephrine, but did not affect presynaptic ₂-adrenoreceptor-mediated responses. In radioligand binding assays using [¹²⁵I]HEAT, -TIA displayed slightly greater potency at the _1B than at the _1A or _1D subtypes. Moreover, although it did not affect the rate of association for [³H]prazosin binding to the _1B-adrenoreceptor, the dissociation rate was increased, indicating non-competitive antagonism by -TIA. N-terminally truncated analogs of -TIA were less active than the full-length peptide, with a large decline in activity observed upon removal of the fourth residue of -TIA (Arg⁴). An alanine walk of -TIA confirmed the importance of Arg⁴ for activity and revealed a number of other residues clustered around Arg⁴ that contribute to the potency of -TIA. The unique allosteric antagonism of -TIA resulting from its interaction with receptor residues that constitute a binding site that is distinct from that of the classical competitive ₁-adrenoreceptor antagonists may allow the development of inhibitors that are highly subtype selective.

Received for publication, May 23, 2003

The atomic coordinates and structure factors (code 1IEN) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed: Institute for Molecular Bioscience, The University of Queensland, St. Lucia 4072, QLD, Australia. Tel.: 61-7-3346-2984; Fax: 61-7-3346-2101; E-mail: r.lewis{at}imb.uq.edu.au.

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