Structural mechanism of voltage-gated ion channels based on the functional structures and their transitions

2023 Fiscal Year Final Research Report

• Project/Area Number: 21H02618
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 47020:Pharmaceutical analytical chemistry and physicochemistry-related
• Research Institution: Keio University
• Principal Investigator: Osawa Masanori 慶應義塾大学, 薬学部(芝共立), 教授 (60361606)
• Co-Investigator(Kenkyū-buntansha): 横川 真梨子 慶應義塾大学, 薬学部(芝共立), 講師 (60648020)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 電位依存性イオンチャネル / 機能構造 / 構造生物学 / 動作メカニズム

Outline of Final Research Achievements

Voltage-gated ion channels (VGICs) are membrane proteins that play important roles in neurotransmission, heart beats, and so on. VGICs have ion-permeation pore with a gate, which opens and closes in response to membrane potential. VGICs regulates membrane potential, by permeate particular ions at appropriate amounts through conformational transitions. However, underlying structural mechanism remained elusive. This study aims to elucidate the structural mechanism by analyzing the resting structure, which emerges at the resting membrane potential, by establishing the methods to stabilize the resting state without membrane potential.
Here, we established a method to stabilize the resting structure by SS-bond linkage of two Cys residues that are introduced by mutagenesis. We analyzed structures of a SS-linked VGIC by electron microscope and characterized its electrophysiological properties.

Free Research Field

構造生物学

Academic Significance and Societal Importance of the Research Achievements

本研究により、VGICが電位依存的な機能を発現する際の構造変化の途中段階を、SS結合で安定化する手法を確立した。これにより、膜電位存在下に一過的に出現する構造についても電子顕微鏡での立体構造解析が可能となった。VGICは、心疾患をはじめとする様々な疾病の治療薬の標的となりうる。したがって、この手法を活用することにより、膜電位存在下で一過的に生じる構造と薬物の相互作用解析が可能となり、革新的な創薬が可能となる。