8OUO

Human TPC2 in Complex with Antagonist (S)-SG-094

8OUO の概要

• エントリーDOI: 10.2210/pdb8ouo/pdb
• EMDBエントリー: 17197
• 分子名称: Two pore channel protein 2, di-heneicosanoyl phosphatidyl choline, 2-{[(4-O-alpha-D-glucopyranosyl-alpha-D-glucopyranosyl)oxy]methyl}-4-{[(3beta,9beta,14beta,17beta,25R)-spirost-5-en-3-yl]oxy}butyl 4-O-alpha-D-glucopyranosyl-alpha-D-glucopyranoside, ... (6 entities in total)
• 機能のキーワード: tpc2, two-pore channel, ion channel, inhibitor, homodimer, metal transport
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 180657.42

構造登録者

Chi, G.,Pike, A.C.W.,Maclean, E.M.,Li, H.,Mukhopadhyay, S.M.M.,Bohstedt, T.,Wang, D.,McKinley, G.,Fernandez-Cid, A.,Duerr, K. (登録日: 2023-04-24, 公開日: 2024-06-12, 最終更新日: 2025-07-02)

主引用文献

Chi, G.,Jaslan, D.,Kudrina, V.,Bock, J.,Li, H.,Pike, A.C.W.,Rautenberg, S.,Krogsaeter, E.,Bohstedt, T.,Wang, D.,McKinley, G.,Fernandez-Cid, A.,Mukhopadhyay, S.M.M.,Burgess-Brown, N.A.,Keller, M.,Bracher, F.,Grimm, C.,Durr, K.L.
Structural basis for inhibition of the lysosomal two-pore channel TPC2 by a small molecule antagonist.
Structure, 32:1137-1149.e4, 2024

PubMed Abstract: Two pore channels are lysosomal cation channels with crucial roles in tumor angiogenesis and viral release from endosomes. Inhibition of the two-pore channel 2 (TPC2) has emerged as potential therapeutic strategy for the treatment of cancers and viral infections, including Ebola and COVID-19. Here, we demonstrate that antagonist SG-094, a synthetic analog of the Chinese alkaloid medicine tetrandrine with increased potency and reduced toxicity, induces asymmetrical structural changes leading to a single binding pocket at only one intersubunit interface within the asymmetrical dimer. Supported by functional characterization of mutants by Ca imaging and patch clamp experiments, we identify key residues in S1 and S4 involved in compound binding to the voltage sensing domain II. SG-094 arrests IIS4 in a downward shifted state which prevents pore opening via the IIS4/S5 linker, hence resembling gating modifiers of canonical VGICs. These findings may guide the rational development of new therapeutics antagonizing TPC2 activity.

PubMed: 38815576
DOI: 10.1016/j.str.2024.05.005

実験手法

ELECTRON MICROSCOPY (3 Å)