7PQU

Ligand-bound human Kv3.1 cryo-EM structure (Lu AG00563)

7PQU の概要

• エントリーDOI: 10.2210/pdb7pqu/pdb
• 関連するPDBエントリー: 7PQT
• EMDBエントリー: 13604 13605
• 分子名称: Potassium voltage-gated channel subfamily C member 1, 1-(4-methylphenyl)sulfonyl-N-(1,3-oxazol-2-ylmethyl)pyrrole-3-carboxamide, POTASSIUM ION, ... (4 entities in total)
• 機能のキーワード: potassium ion channel, voltage gated, drug target, membrane protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 237070.60

構造登録者

Botte, M.,Huber, S.,Bucher, D.,Klint, J.K.,Rodriguez, D.,Tagmose, L.,Chami, M.,Cheng, R.,Hennig, M.,Abdul Rhaman, W. (登録日: 2021-09-20, 公開日: 2022-08-17, 最終更新日: 2024-07-17)

主引用文献

Botte, M.,Huber, S.,Bucher, D.,Klint, J.K.,Rodriguez, D.,Tagmose, L.,Chami, M.,Cheng, R.,Hennig, M.,Abdul Rahman, W.
Apo and ligand-bound high resolution Cryo-EM structures of the human Kv3.1 channel reveal a novel binding site for positive modulators.
Pnas Nexus, 1:pgac083-pgac083, 2022

PubMed Abstract: Kv3 ion-channels constitute a class of functionally distinct voltage-gated ion channels characterized by their ability to fire at a high frequency. Several disease relevant mutants, together with biological data, suggest the importance of this class of ion channels as drug targets for CNS disorders, and several drug discovery efforts have been reported. Despite the increasing interest for this class of ion channels, no structure of a Kv3 channel has been reported yet. We have determined the cryo-EM structure of Kv3.1 at 2.6 Å resolution using full-length wild type protein. When compared to known structures for potassium channels from other classes, a novel domain organization is observed with the cytoplasmic T1 domain, containing a well-resolved Zinc site and displaying a rotation by 35°. This suggests a distinct cytoplasmic regulation mechanism for the Kv3.1 channel. A high resolution structure was obtained for Kv3.1 in complex with a novel positive modulator Lu AG00563. The structure reveals a novel ligand binding site for the Kv class of ion channels located between the voltage sensory domain and the channel pore, a region which constitutes a hotspot for disease causing mutations. The discovery of a novel binding site for a positive modulator of a voltage-gated potassium channel could shed light on the mechanism of action for these small molecule potentiators. This finding could enable structure-based drug design on these targets with high therapeutic potential for the treatment of multiple CNS disorders.

PubMed: 36741467
DOI: 10.1093/pnasnexus/pgac083

実験手法

ELECTRON MICROSCOPY (3.03 Å)