ORGN 586 |
| Stefan N Gradl1, Dirk Trauner2, Ehud Y Isacoff3, Maria L Garcia4, and John P Felix4. (1) Department of Chemistry, University of California at Berkeley, Berkeley, CA 94720, (2) Department of Chemistry, University of Califonia, Berkeley, 602 Latimer Hall, Berkeley, CA 94720-1460, (3) Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720-1460, (4) Department of Ion Channels, Merck Research Laboratories, Rahway, NJ 07065 |
| Potassium channels provide an ideal platform with which to probe the principles of protein surface recognition. The recent crystal structures by MacKinnon et. al. gave a detailed view of these transmembrane proteins and established their tetrameric nature. Scorpion toxins are natural peptide blockers of K+ channels but lack their fourfold symmetry. From double cycle mutant thermodynamic studies of toxins, “hot spots” can be identified on the surface of these channels. We have designed and synthesized fourfold symmetric ligands that mimic the scorpion toxins while taking advantage of a strong polyvalency effect. These compounds inhibit binding of radiolabeled Hongotoxin to Kv1.3 at nanomolar concentrations, potentially leading to immunosuppressive agents. The compounds block potassium current through the Shaker channel expressed in Xenopus oocytes. Our current progress in the synthesis and binding studies of these molecules will be described. |
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Molecular Recognition and Self-Assembly
8:00 AM-12:00 PM, Thursday, April 1, 2004 Anaheim Convention Center -- 303A, Oral
Division of Organic Chemistry |
