8DFL

Structure of human Kv1.3 with A0194009G09 nanobodies (alternate conformation)

8DFL の概要

• エントリーDOI: 10.2210/pdb8dfl/pdb
• EMDBエントリー: 25417
• 分子名称: Potassium voltage-gated channel subfamily A member 3,Green fluorescent protein fusion, Nanobody A0194009G09, POTASSIUM ION (3 entities in total)
• 機能のキーワード: ion channel, immune system
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 435589.09

構造登録者

Meyerson, J.R.,Selvakumar, P. (登録日: 2022-06-22, 公開日: 2022-07-13, 最終更新日: 2024-10-16)

主引用文献

Selvakumar, P.,Fernandez-Marino, A.I.,Khanra, N.,He, C.,Paquette, A.J.,Wang, B.,Huang, R.,Smider, V.V.,Rice, W.J.,Swartz, K.J.,Meyerson, J.R.
Structures of the T cell potassium channel Kv1.3 with immunoglobulin modulators.
Nat Commun, 13:3854-3854, 2022

PubMed Abstract: The Kv1.3 potassium channel is expressed abundantly on activated T cells and mediates the cellular immune response. This role has made the channel a target for therapeutic immunomodulation to block its activity and suppress T cell activation. Here, we report structures of human Kv1.3 alone, with a nanobody inhibitor, and with an antibody-toxin fusion blocker. Rather than block the channel directly, four copies of the nanobody bind the tetramer's voltage sensing domains and the pore domain to induce an inactive pore conformation. In contrast, the antibody-toxin fusion docks its toxin domain at the extracellular mouth of the channel to insert a critical lysine into the pore. The lysine stabilizes an active conformation of the pore yet blocks ion permeation. This study visualizes Kv1.3 pore dynamics, defines two distinct mechanisms to suppress Kv1.3 channel activity with exogenous inhibitors, and provides a framework to aid development of emerging T cell immunotherapies.

PubMed: 35788586
DOI: 10.1038/s41467-022-31285-5

実験手法

ELECTRON MICROSCOPY (3.25 Å)