Structural Insights into Human Acid-1 sensing Ion Channel 1a Inhibition by Snake Toxin Mambalgin1

Acid-sensing ion channels (ASICs) are proton-gated cation channels that are involved in diverse neuronal processes including pain sensing. Peptide toxin Mambalgin1 (Mamba1) from black mamba snake venom can reversibly inhibit the conductance of ASICs, showing an analgesic effect. However, the detailed inhibitory mechanism of Mamba1 on ASIC1s, especially how Mamba1 binding to extracellular domain affects the conformational changes of the transmembrane domain of ASICs remains elusive. Here, we present single-particle cryo-EM structures of human ASIC1a (hASIC1a) and hASIC1a-Mamba1 complex at resolutions of 3.56 and 3.90 Å, respectively. The structures revealed the inhibited conformation of hASIC1a upon Mamba1 binding. The combination of the structural and physiological data indicates that Mamba1 prefers to bind hASIC1a in a closed state and reduces the proton sensitivity of the channel, representing a closed-state trapping mechanism.