[3P-1] ポスター3（3P-01ー3P-47）

[3P-20] Gating-modifier toxin APETx1による電位依存性カリウムイオンチャネルhERG阻害機構の解析

松村 一輝¹, 下村 拓史², 久保 義弘², 岡 貴之³, 小林 直宏^4,5, 今井 駿輔⁶, 簗瀬 尚美¹, 秋元 まどか¹, 福田 昌弘¹, 横川 真梨子¹, 池田 和由¹, 栗田 順一⁷, 西村 善文⁷, 嶋田 一夫⁶, ^○大澤 匡範¹ (1.慶應大院・薬, 2.生理研・分子細胞生理, 3.ナニオンテクノロジーズジャパン, 4.阪大・蛋白研, 5.理研・放射光科学研, 6.東大・院薬, 7.横浜市大・院生命医科学)

Human ether-a-go-go-related gene potassium channel 1 (hERG) is a voltage-gated potassium channel, the voltage-sensing domain (VSD) of which is targeted by a gating-modifier toxin, APETx1. APETx1 is a 42-residue peptide toxin of Anthopleura elegantissima and inhibits hERG by stabilizing the resting state. Mutational analysis of APETx1 could not be conducted as only natural resources have been available until now. Therefore, it remains unclear where and how APETx1 interacts with the VSD in the resting state. We established a method for preparing recombinant APETx1 and determined the NMR structure of the recombinant APETx1, which is structurally equivalent to the natural product. Electrophysiological analyses using wild type and mutants of APETx1 and hERG revealed that F15, Y32, F33, and L34 in APETx1, and F508 and I521 in hERG, in addition to E518, play key roles in hERG inhibition by APETx1. Our hypothetical docking models of the APETx1-VSD complex are consistent to the results of mutational analysis. These results would help advance understanding of the inhibitory mechanism of APETx1, which could provide a structural basis for designing novel ligands targeting the VSDs of hERG.