Allostery refers to coupled changes in function and/or structural dynamics at protein active sites in response to perturbations, such as ligand binding, mutations, post-translational modifications, light absorption, or mechanical perturbations, at a structurally distant site (a.k.a. allosteric site). Allosteric modulation is fundamental to the function of ion channels, membrane receptors, signaling proteins, and transcription factors. They are implicated in several human disorders and now, allosteric sites are being explored as better drug targets compared to the orthosteric ligand binding sites because of the ease in engineering them to improve selectivity without interfering with the binding of endogenous ligands.

nAChRs are typical allosteric proteins. The ion channel pore is in the transmembrane domain (TMD), ~50 Å away from the neurotransmitter binding site (TBS). Agonist binding to the TBS triggers a global ‘gating’ conformational change that rearranges the channel pore to allow ion conduction. Our lab is trying to understand how the information about ligand binding is transmitted from the TBS to the pore (allosteric communication) during gating transition. Likewise, how allosteric modulators change the ligand binding at the TBS is largely unknown. We are exploring a common molecular mechanism that may explain such intriguing signal transduction processes. Our recent work elucidates the potential presence of a live wire like allosteric communication network of amino acids from the transmitter binding site to the channel pore in Understanding the mechanism of ligand sensing and the downstream allosteric communication will provide deep insight into the inner workings of the allosteric proteins and their physiological functions in the cells.