The primary goals of this project remain to develop structural models of membrane channel proteins and to work with experimentalist to test and improve these models. We use a long term iterative approach in which models are continuously made more precise. The projects for which this approach has enjoyed the most success are those involving homologous voltage-gated potassium (K), sodium (Na), and calcium (Ca) channels. Almost all our initial predictions about their transmembrane topology and about which segments form ligand binding sites, ion selective regions, and gating mechanisms have now been confirmed experimentally. Now many laboratories have begun to use mutagenesis and other methods to analyze the structure-function properties of these proteins. Based on this wealth of new data, we have developed a new generation of more precise models of the entire transmembrane region of most families of K+ channels in open, closed, and inactivated conformations. We have also started a number of other new modeling projects and are collaborating with several laboratories to test them. These collaborations are with Thomas Kuner in Peter Seaberg's group in Heidelberg, Germany to model the NMDA receptor; with J. Peter Ruppersberg laboratory in T?bingen, Germany to model inactivation of K+ channels; with Bernard Rossier's and Laurent Schild's laboratory in Lausanne, Switzerland, to develop and test models of epithelial Na channels which are unrelated to the voltage-gated Na channels we have modeled previously; with Kathryn Sandberg at Georgetown University Medical Center to model the angiotensin receptor; with Saul Goldman at Guelph University and Peter Backx at Toronto University to model K+ permeation mechanisms; with Ching Kung's laboratory at the University of Wisconsin, to develop models of stretch-activated channels from bacteria; and with R. Alan North of the Glaxo Institute for Molecular Biology in Geneva, Switzerland to model P2X receptors. We are also collaborating with Robert Blumenthal's and Dimiter Dimitrov's group (LECB) to model viral fusion mechanisms and chemokine receptors that act as coreceptors during HIV membrane fusion.
