Targeting Nav channels for pain relief (#119)
Voltage-gated sodium (Nav) channels are responsible for the initiation and propagation of action potentials. Associated with a variety of disorders, Nav channels are targeted by a variety of FDA-approved drugs and natural toxins. Employing the modern methods of cryo-EM, we determined high resolution structures of a number of eukaryotic and eventually human Nav channels in complex with auxiliary subunits, toxins, and drugs, which reveal the mode of action of representative Nav modulators. Based on the structural discovery, we suggest a “door-wedge” allosteric blocking mechanism for fast inactivation of Nav channels. Structural comparison of the conformationally distinct Nav channels provides important insights into the electromechanical coupling mechanism of Nav channels, offers the 3D template to map hundreds of disease mutations, and will aid rational design of next-generation pain killers.
