Structure and properties of omega-agatoxin IVB, a new antagonist of P- type calcium channels

ME Adams, IM Mintz, MD Reily, V Thanabal and BP Bean

Department of Entomology, University of California, Riverside 92521.

A new peptide antagonist of voltage-activated calcium channels was purified from venom of the funnel web spider, Agelenopsis aperta. This 48-amino acid peptide, omega-agatoxin (omega-Aga)-IVB, was found to be a potent (Kd, approximately 3 nM) blocker of P-type calcium channels in rat cerebellar Purkinje neurons but had no activity against T-type, L- type, or N-type calcium channels in a variety of neurons. The calcium channel-blocking properties of omega-Aga-IVB were similar to those of another toxin, omega-Aga-IVA, which has 71% amino acid identity with omega-Aga-IVB. The 10-fold greater abundance of omega-Aga-IVB in venom allowed structural studies using NMR spectroscopy. The three- dimensional structure derived from NMR data resulted in a proposed disulfide bond configuration for the peptide. Although omega-Aga-IVB has fewer basic and more acidic residues than does omega-Aga-IVA, the two toxins show conservation of positively charged residues in a mid- peptide region that is predicted to form one face of the omega-Aga-IVB molecule. This region may be crucial for high affinity binding to the P- type calcium channel. In contrast, the amino termini of the two toxins have different charges and seem unlikely to be involved in binding to the channel.

Volume 44, Issue 4, pp. 681-688, 10/01/1993
Copyright © 1993 by American Society for Pharmacology and Experimental Therapeutics

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