Research Projects

Allosteric communication is critical to the function of cell membrane receptors, ion channels, signaling networks, and gene expression machinery, with implications in various human disorders. Allosteric sites are increasingly favored as drug targets due to their ability to improve selectivity without disrupting endogenous ligand binding. Acetylcholine receptors (AChRs), expressed at nerve-muscle junctions (NMJ), are exemplary allosteric proteins and part of the pentameric ligand-gated ion channel (LGIC) superfamily, comprising (α1)₂βδε/γ subunits. AChRs have two neurotransmitter binding sites (TBS) at α-δ and α-ε (adult) or α-γ (fetal) subunit interfaces in the extracellular domain (ECD), while the ion channel pore lies ~50 Å away in the transmembrane domain (TMD). How agonist binding at the TBS transmits signals to the pore during gating transition remains an intriguing question. Preliminary findings suggest a dynamic, well-defined energy network connecting the TBS to the channel gate, forming an allosteric communication pathway. This study hypothesizes that AChRs utilize distinct allosteric protein side-chain networks to mediate ligand-specific signaling. The receptor harnesses a fraction of ligand chemical energy—termed efficiency—to drive conformational changes during ligand-protein complex formation. Notably, AChRs exhibit varying efficiency values for different ligand classes, potentially triggering distinct allosteric pathways and functional outcomes. Exploring efficiency-based ligand classification may serve as a predictive tool for identifying novel therapeutic candidates for AChRs and other LGICs, bypassing the need for random library screening. This proposal aims to investigate these mechanisms in neuromuscular AChRs using single-channel patch-clamp electrophysiology, high-throughput screening, thermodynamic studies, and computational modeling to uncover the principles underlying ligand-specific allosteric communication.