STRUCTURAL MODEL OF THE OUTER VESTIBULE AND SELECTIVITY FILTER OF THESHAKER VOLTAGE-GATED K+ CHANNEL

A new generation of structural models were developed of the outer vest ibule and ion-selective portion of the voltage-gated Shaker K+ channel . Some features of these models are similar to those that we have deve loped previously [Durrel S. R. and Guy H. R. (1992) Biophys. J. 62, 23 8-250; Guy H. R. (1990) In Monovalent Cations in Biological Systems (P asternak C. A., Ed.), pp. 31-58, CRC Press, Boca Raton, FL; Guy Ii. R. and Durell S. R. (1994) In Molecular Evolution of Physiological proce sses (Fambrough D., Ed.), pp. 197-212, The Rockefeller University Pres s, NY; Guy H. R. and Durell S. R. (1995) In ion Channels and Genetic D iseases (Dawson D., Ed.), pp. 1-16, The Rockefeller University Press, NY] and other features were modified to make the models more consisten t with recent experimental findings. The first part of the P segment i s postulated, as always, to form a short alpha helix that spans only t he outer portion of the membrane. The helix is tilted so that its C-te rminal is nearer the pore than its N-terminal. The latter part of the P segment, P2, is postulated to have a relatively elongated conformati on that is positioned approximately parallel to the axis of the pore. Four of the P2 segments assemble to form an ion-selective region that has two narrow regions; one formed by the Y445 side-chains at the oute r entrance of the pore and one formed by the backbone of the T442 resi dues near the innermost part of the P segments. The S6 segment is post ulated to form two alpha helices. The first S6 helix packs next to the P segments in our models. The NMR structures of two scorpion toxins, charybdotoxin and agitoxin 2, have been docked into the models of the outer vestibules. The shape of the outer vestibule has been modeled so that specific toxin-channel residue-residue interactions correspond t o those that have been identified experimentally.