ИСТИНА

Voltage-gated potassium channel Kv10.2 belongs to the family EAG channels. Mutations in this channel leads to the development of neurological disease and certain tumors. Directed drug design requires knowledge of the details of the three-dimensional structure of the channel. EAG family members are characterized by long, with respect to other families, N- and C-terminal intracellular amino acid sequences which include structural and functional domains. N-terminal domain in PAS Kv10 plays an important role in the activation, and is believed to alter the rate of deactivation, possibly by binding to the linker S4-S5. In this study, we have 3D structure of the human truncated channel Kv10.2 using microscopy of single molecules. In this channel there is no N-terminal cytoplasmic domain PAS (Kv10.2ΔPAS), but the channel forms a tetramer. Previously, we have shown that the cytoplasmic domains of full-length channel Kv10.2 form a structure of the type "hanging gondola." The cytoplasmic portion includes connecting PAS domains and сNBD. Removal PAS domain leads to a conformational change in the cytoplasmic portion of the channel as well as localization suggests certain cytoplasmic domains are part of the full-length channel. For interpretation of the 3D structures we used homology modeling and molecular dynamics simulation. There are several templates available to the moment including eag domain-CNBHD complex of the mouse EAG1 channel, full-length Shaker potassium channel Kv1.2, C-linker/CNBHD of zELK channels and others. But there are still no templates for many fragments that led to necessity of partial de novo modeling. Analysis of molecular trajectory allowed estimating dynamical characteristics of channel, supposing interdomain interactions. This work was supported by the Ministry of Education and Science of the Russian Federation. Unique project identifier - RFMEEI61615X0044.