Structural modeling of Nav1.5 pore domain in closed state

Xiaofeng Ji; Yanzhao Huang; Jun Sheng

doi:10.52601/bpr.2021.200021

Structural modeling of Na_v1.5 pore domain in closed state

Biophys Rep. 2021 Aug 31;7(4):341-354. doi: 10.52601/bpr.2021.200021.

Authors

Xiaofeng Ji¹, Yanzhao Huang², Jun Sheng¹

Affiliations

¹ Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Qingdao 266071, Shandong, China.
² School of Physics, Huazhong University of Science and Technology, Wuhan 430074, China.

Abstract

The voltage-dependent cardiac sodium channel plays a key role in cardiac excitability and conduction and it is the drug target of medically important. However, its atomic- resolution structure is still lack. Here, we report a modeled structure of Na_v1.5 pore domain in closed state. The structure was constructed by Rosetta-membrane homology modeling method based on the template of eukaryotic Na_v channel Na_vPaS and selected by energy and direct coupling analysis (DCA). Moreover, this structure was optimized through molecular dynamical simulation in the lipid membrane bilayer. Finally, to validate the constructed model, the binding energy and binding sites of closed-state local anesthetics (LAs) in the modeled structure were computed by the MM-GBSA method and the results are in agreement with experiments. The modeled structure of Na_v1.5 pore domain in closed state may be useful to explore molecular mechanism of a state-dependent drug binding and helpful for new drug development.

Keywords: Closed state; Direct coupling analysis; Drug binding; Homology modeling; Local anesthetics; Nav1.5 ion channel.