Ion Transport from Physics to Physiology: the Missing Rungs in the Ladder
Molecular mechanism of modulation of pentameric ligand gated ion channels: Insights from electrophysiology, structural biology and molecular dynamicsErik Lindahl
KTH/Stockholm University, Stockholm, Sweden, Sweden
Ligand-gated ion channels exhibit a wide range of responses, and in particular their allosteric modulation is quite complex: The very same allosteric modulator can either inhibit or potentiate receptors depending on the channel family, single-residue mutations in the transmembrane domain, and even the concentration of the modulating compound. This makes ligand-gated ion channels (and in particular prokaryotic model channels) fascinating model systems to understand how structure and function are related to dynamics and conformational rearrangements between domains, in particular in the context of allosteric modulation. I will present our work on trying to understand these systems using a combination of computational modeling, simulations, free energy calculations as well as electrophysiology experiments. We have been able to show that ligand-gated ion channels likely have separate modulatory sites (in addition to the primary agonist-binding site), and that channel inhibition vs. potentiation can be explained by different actions. By using computational design we then design mutations that alter these properties in model channels, and selectively target allosteric modulators to one site or another. This is one of the first examples where we can use computations not only to screen and optimize binding in a specific site, but target the efficacy of the drugs on a biological process. I will also discuss recent results where we are trying to use the rapidly increasing amount of structural biology data to study entire ensembles of structures to understand how different channel states are related, and how we are trying to explore the relations between gating and channel pore properties. This leads to interesting insights about conformational selectivity and dynamics in complex receptors, with potential implications for drug design particularly in anesthesia and addiction disease.