Fig. 4. The conformational change of the thumb domain of cASIC1a.

a Superimposition of cASIC1a in different states illustrates the movement of the thumb domain triggered by mambalgin-1 binding. The thumb domain is shown cartoon and the other parts of cASIC1a as well as mambalgin1 in ribbon. The apo-cASIC1a (PDB 4NYK), PcTx1-bound cASIC1a (PDB 4FZ1), MitTx1-bound cASIC1a (PDB 4NTY) and mambalgin-1-bound cASIC1a are colored in magenta, yellow, light blue and cyan, respectively. b Superimposition of the thumb domain and its adjacent regions in the β-ball domain of apo-cASIC1a (magenta) and mambalgin-1-bound cASIC1a (cyan). The Cα atoms of several key residues involved in acid sensing are shown as spheres, and the distances between these Cα atoms are indicated. c A proposed allosteric mechanism for the inhibition of ASIC1a channel by mambalgin-1. Mambalgin-1 binding to the ASIC1a channel triggers the movement of the thumb domain, which disrupts the connecting residue pairs in the acidic pocket and results in an expanded pocket. This conformational change may lead to the decoupling of domain rearrangement, trap the channel in a closed state. Domains of a single subunit of ASIC1a are shown as yellow for Palm, blue for Knuckle, purple for Finger, olive for β–ball, green for Thumb and gray for Transmembrane domains. The approximate position of the acidic pocket is indicated by black dashed lines. The red stars represent key residue pairs that connect β–ball and thumb domain