Structure-function studies of potassium channels and toxin inhibitors 

Potassium channels (K+-channels) are homotetrameric membrane-embedded assemblies that control the influx/efflux of K+ ions in cells and play critical roles in all biological systems. While much is known about the structural basis for ion selection and gating in such channels, their interaction with various inhibiting toxins is rather enigmatic because of the lack of toxin-channel complex structures. In our lab we aim to unravel the secrets of how toxins bind to the channel opre in a specific manner and block ion conduction. KcsA is an exhaustively studied bacterial channel which has also been used as a scaffold for modeling voltage-gated channels by replacing the extracellular 'turret' region with the analogous human amino acid sequence. Currently we are investigating the interactions of KcsA with Hui1, a de novo toxin discovered in a phage-library screen, and of Kv1.3 with ShK, a natural toxin from the sea anemone Stichodactyla helianthus. Understanding how each channel recognizes and specifically binds its respective toxin will allow us to design toxins with improved affinity and/or selectivity, an ability that carries important therapeutical implications.

Publications:

Sher, I.;† Chang, S.-C.;† Li, Y.; Chhabra, S.; Palmer III, A.G.;.Norton, R.S. and Chill, J.H. Conformational flexibility in the binding surface of the potassium channel blocker ShK. ChemBioChem, 2014, 15(16):2402-2410. Featured on cover. †Equal contribution.

Meirovitch, E.: Tchaicheeyan, O.; Sher, I.; Norton, R.S.; Chill, J.H. Structural dynamics of the potassium channel blocker ShK: SRLS analysis of 15N relaxation. J. Phys. Chem. B 2015, 119, 15130-15137.

Zhao, R.; Dai, H.; Mendelman, N.; Cuello, L.; Chill, J.H.; Goldstein, S. Designer and natural peptide toxin blockers of the KcsA potassium channel identified by phage-display. Proc. Natl. Acad. Sci. 2015, 112(50), E7013-7021.

Bar Ilan University, Department of Chemistry, Building 211, Room 314 Ramat Gan, Israel, 5290002