Structural basis of the selective block of Kv1.2 by maurotoxin from computer simulations.
The 34-residue polypeptide maurotoxin (MTx) isolated from scorpion venoms selectively inhibits the current of the voltage-gated potassium channel Kv1.2 by occluding the ion conduction pathway. Here using molecular dynamics simulation as a docking method, the binding modes of MTx to three closely related channels (Kv1.1, Kv1.2 and Kv1.3) are examined. We show that MTx forms more favorable electrostatic interactions with the outer vestibule of Kv1.2 compared to Kv1.1 and Kv1.3, consistent with the selectivity of MTx for Kv1.2 over Kv1.1 and Kv1.3 observed experimentally. One salt bridge in the bound complex of MTx-Kv1.2 forms and breaks in a simulation period of 20 ns, suggesting the dynamic nature of toxin-channel interactions. The toxin selectivity likely arises from the differences in the shape of the channel outer vestibule, giving rise to distinct orientations of MTx on block. Potential of mean force calculations show that MTx blocks Kv1.1, Kv1.2 and Kv1.3 with an IC(50) value of 6 µM, 0.6 nM and 18 µM, respectively.
Research School of Biology, Australian National University, Canberra, Australian Capital Territory, Australia. rong.chen@anu.edu.au
Rong
R
Chen
Shin-Ho
SH
Chung
D000595:Amino Acid Sequence; D001665:Binding Sites; D051663:Kv1.2 Potassium Channel / Q000737:chemistry*; D051664:Kv1.3 Potassium Channel / Q000378:metabolism; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D012604:Scorpion Venoms / Q000737:chemistry* / Q000378:metabolism
D051663:Kv1.2 Potassium Channel; D051664:Kv1.3 Potassium Channel; D012604:Scorpion Venoms; C104498:maurotoxin