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Volume 272, Number 18, Issue of May 2, 1997 pp. 12014-12023
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

Structure-Function Relationships of omega -Conotoxin GVIA
SYNTHESIS, STRUCTURE, CALCIUM CHANNEL BINDING, AND FUNCTIONAL ASSAY OF ALANINE-SUBSTITUTED ANALOGUES

(Received for publication, November 15, 1996, and in revised form, February 6, 1997)

Michael J. Lew Dagger , James P. Flinn Dagger , Paul K. Pallaghy , Roger Murphy Dagger , Sarah L. Whorlow Dagger , Christine E. Wright Dagger , Raymond S. Norton and James A. Angus Dagger

From the Dagger  Department of Pharmacology, University of Melbourne and the  Biomolecular Research Institute, 343 Royal Parade, Parkville 3052, Victoria, Australia

The structure-function relationships of the N-type calcium channel blocker, omega -conotoxin GVIA (GVIA), have been elucidated by structural, binding and in vitro and in vivo functional studies of alanine-substituted analogues of the native molecule. Alanine was substituted at all non-bridging positions in the sequence. In most cases the structure of the analogues in aqueous solution was shown to be native-like by 1H NMR spectroscopy. Minor conformational changes observed in some cases were characterized by two-dimensional NMR. Replacement of Lys2 and Tyr13 with Ala caused reductions in potency of more than 2 orders of magnitude in three functional assays (sympathetic nerve stimulation of rat isolated vas deferens, right atrium and mesenteric artery) and a rat brain membrane binding assay. Replacement of several other residues with Ala (particularly Arg17, Tyr22 and Lys24) resulted in significant reductions in potency (<100-fold) in the functional assays, but not the binding assay. The potencies of the analogues were strongly correlated between the different functional assays but not between the functional assays and the binding assay. Thus, the physiologically relevant assays employed in this study have shown that the high affinity of GVIA for the N-type calcium channel is the result of interactions between the channel binding site and the toxin at more sites than the previously identified Lys2 and Tyr13.


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