High-resolution structures using cryo-EM guide drug development for neuromyelitis optica (NMO)

Neuromyelitis Optica (NMO) is an autoimmune disease where human antibodies self-target the water channel AQP4. This leads to induction of compliment activation ultimately resulting in death of astrocytes in the brain resulting in vision and other neurological symptoms. There is a panel of these human autoantibodies, and the mechanism of immune response varies from antibody to antibody. We determined molecular structures of AQP4 apo and AQP4 bound to patient derived autoantibodies in nanodiscs using cryo-EM. Our data provides high-resolution details of the interface between AQP4 and autoantibodies for drug designing purposes. Here, we highlight the structural differences in the way these antibodies bind and hence dissecting the mechanism of immune responses generated to develop a better drug-development platform. These are the first structures of a channel demonstrating an autoimmune disease.