Acid-sensing ion channels (ASICs) are potential novel therapeutic targets in a range of pathologies including ischemic stroke, spinal cord injury, chronic pain, multiple sclerosis, rheumatoid arthritis, and migraine. Nonetheless, there are no drugs available on the market that target these channels selectively. A hurdle in the development of selective ASIC drugs is the lack of adequate and reliable structural data of these pH sensitive ion channels in their multiple conformational and protonation states. ASICs like most ion channels are membrane proteins, and therefore difficult to study in the absence of a lipid bilayer. The ASIC thumb is a cysteine-rich domain, and its two α-helices encompass the “acidic pocket” that collapses upon extracellular acidification. It is known to bind to two highly potent and selective venom peptide toxins PcTx1 and MitTx. All the structural data available to date are from a single isoform of ASIC (1a) derived using X-ray crystallography and electron microscopy. Our research proposes a novel reductionist approach to show that the thumb domain in isolation in solution retains the structure and ligand binding properties of the full length ASIC, but is much simpler to produce and study in isolation – providing an avenue to study other ASICs that have proven inaccessible by existing approaches. Here, I will present the first structure of the isolated thumb domain of ASIC1a in solution determined by nuclear magnetic resonance (NMR) spectroscopy. NMR further allows us to observe the structure and ligand binding properties of these acid sensing ion channels in response to changes in pH. Finally, we will be able to monitor molecular motion at an atomic level in a region of the channel that has been proposed to undergo conformational changes in response to pH and ligand binding.