7P60

Structure of homomeric LRRC8A Volume-Regulated Anion Channel in complex with synthetic nanobody Sb4 at 1:0.5 ratio

7P60 の概要

• エントリーDOI: 10.2210/pdb7p60/pdb
• EMDBエントリー: 13202 13203 13208 13212 13213
• 分子名称: Volume-regulated anion channel subunit LRRC8A, synthetic nanobody Sb4 (2 entities in total)
• 機能のキーワード: lrrc8 family, volume-regulated anion channel, leucine-rich repeat, sybody, cryo-em, membrane protein
• 由来する生物種: Mus musculus (Mouse); 詳細
• タンパク質・核酸の鎖数: 9
• 化学式量合計: 615873.10

構造登録者

Deneka, D.,Rutz, S.,Sawicka, M. (登録日: 2021-07-15, 公開日: 2021-09-15, 最終更新日: 2025-07-02)

主引用文献

Deneka, D.,Rutz, S.,Hutter, C.A.J.,Seeger, M.A.,Sawicka, M.,Dutzler, R.
Allosteric modulation of LRRC8 channels by targeting their cytoplasmic domains.
Nat Commun, 12:5435-5435, 2021

PubMed Abstract: Members of the LRRC8 family form heteromeric assemblies, which function as volume-regulated anion channels. These modular proteins consist of a transmembrane pore and cytoplasmic leucine-rich repeat (LRR) domains. Despite their known molecular architecture, the mechanism of activation and the role of the LRR domains in this process has remained elusive. Here we address this question by generating synthetic nanobodies, termed sybodies, which target the LRR domain of the obligatory subunit LRRC8A. We use these binders to investigate their interaction with homomeric LRRC8A channels by cryo-electron microscopy and the consequent effect on channel activation by electrophysiology. The five identified sybodies either inhibit or enhance activity by binding to distinct epitopes of the LRR domain, thereby altering channel conformations. In combination, our work provides a set of specific modulators of LRRC8 proteins and reveals the role of their cytoplasmic domains as regulators of channel activity by allosteric mechanisms.

PubMed: 34521847
DOI: 10.1038/s41467-021-25742-w

実験手法

ELECTRON MICROSCOPY (3.8 Å)