TOPOLOGY OF THE PORE-REGION OF A K-DERIVED STRUCTURES OF SCORPION TOXINS( CHANNEL REVEALED BY THE NMR)

The architecture of the pore-region of a voltage-gated K+ channel, Kv1 .3, was probed using four high affinity scorpion toxins as molecular c alipers. We established the structural relatedness of these toxins by solving the structures of kaliotoxin and margatoxin and comparing them with the published structure of charybdotoxin; a homology model of no xiustoxin was then developed. Complementary mutagenesis of Kv1.3 and t hese toxins, combined with electrostatic compliance and thermodynamic mutant cycle analyses, allowed us to identify multiple toxin-channel i nteractions. Our analyses reveal the existence of a shallow vestibule at the external entrance to the pore. This vestibule is similar to 28- 32 Angstrom wide at its outer margin, similar to 28-34 Angstrom wide a t its base, and similar to 4-8 a deep. The pore is 9-14 Angstrom wide at its external entrance and tapers to a width of 4-5 Angstrom at a de pth of similar to 5-7 Angstrom from the vestibule. This structural inf ormation should directly aid in developing topological models of the p ores of related ion channels and facilitate therapeutic drug design.