Ion channels are the second-largest class of drug targets following GPCRs. They play pivotal roles in various physiological processes and are implicated in many health and disease states, including developmental disorders, neurodegenerative diseases, and even cancer.
Ion channel activation and modulation are fundamental processes in cellular physiology. Mechanisms of activation include membrane potential, ion concentration, temperature, ligands and mechanical force; channel activity can be modulated by various factors, including post-translational modification or drugs and small molecules. Understanding the mechanisms of ion channel activation and modulation is essential for elucidating their roles in health and disease and to potentially identify treatments for conditions characterized by ion channel dysfunction.
Together with traditional techniques such as electrophysiology and fluorescence resonance energy transfer (FRET), structure knowledge is becoming indispensable for understanding the molecular basis of ion channel function, pharmacology, and disease.
Understanding Ion Channel Structure through Cryo-EM Structure Determination
There are several challenges when trying to determine the structure of ion channels. Their size, conformational complexity and variability, and difficulties in protein expression, purification and stabilization, make structure determination using crystallography and NMR quite challenging. In the last 10 years, cryo-EM has revolutionized the ability to capture the conformational landscape of large and flexible proteins, including membrane proteins like ion channels. Cryo-EM allows for the visualization of such large and dynamic macromolecular complexes in near-native conditions, providing insights into their structure and function. One single cryo-EM experiment can capture multiple conformational states and dynamic movements, providing insights into the gating mechanisms, allosteric regulation, and interactions with ligands or modulators. Recent advances in cryo-EM instrumentation, image analysis techniques and data processing algorithms have led to significant improvements in resolution and structural details. Cryo-EM structures of ion channels have reached near-atomic resolution, allowing for the understanding of key structural features as well as detailed ligand interactions. In addition, recent developments in the ability of studying conformational heterogeneity within the same sample allows for the identification and characterization of different functional states and subpopulations, essential for the understanding of ion channels complex biology.
Structural knowledge of ion channels in complex with pharmacological agents, toxins, or ligands can provide valuable insights into drug binding sites, mechanisms of action, and structure-activity relationships. These structures may aid in rational drug design and the development of novel therapeutics targeting ion channels in various diseases.
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