Gating of ion channels and shutdown of G-protein-coupled receptors revealed by kinetic DEER spectroscopy.

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Membrane receptors (like G-protein-coupled receptors) and ion channels involved in cellular signaling become activated by binding of ligands. The structure of a few receptors and ion channels is known at molecular or atomic resolution. However, except for a few cases, the conformational changes during transition from one to another signaling state at Ångström and micro- to millisecond resolution are not known. I propose to use time-resolved pulsed electron paramagnetic resonance (EPR) techniques (PELDOR or DEER) to resolve these conformational changes in two different signaling processes: the opening of cyclic nucleotidesensitive ion channels and the shut-down of the visual pigment rhodopsin by the stop-protein arrestin. This approach has the potential to delineate the sequence of conformational changes in many signaling proteins and, thereby, serve as a model. The project is challenging and requires the cooperation of several experts in EPR spectroscopy, channel biophysics, protein chemistry, computational biophysics, and cellular signaling.