9JO3

Cryo-EM structure of human BKca channel-compound 10b complex

これはPDB形式変換不可エントリーです。

9JO3 の概要

• エントリーDOI: 10.2210/pdb9jo3/pdb
• EMDBエントリー: 61642
• 分子名称: Calcium-activated potassium channel subunit alpha-1, MAGNESIUM ION, CALCIUM ION, ... (6 entities in total)
• 機能のキーワード: bkca channel, compound 10b, cryo-em, 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: 513887.32

構造登録者

Kim, S.,Park, S.,Lee, N.Y.,Lee, E.Y.,Lee, N.,Roh, E.C.,Kim, Y.G.,Kim, H.J.,Jin, M.S.,Park, C.S.,Kim, Y.C. (登録日: 2024-09-24, 公開日: 2025-02-26, 最終更新日: 2025-06-25)

主引用文献

Park, S.B.,Lee, N.Y.,Lee, E.Y.,Kim, S.,Lee, N.,Roh, E.C.,Kim, Y.G.,Kim, H.J.,Jin, M.S.,Park, C.S.,Kim, Y.C.
Discovery of Diphenyl Ether Derivatives as Novel BK Ca Channel Activators: Structure-Activity Relationship, Cryo-EM Complex Structures, and In Vivo Animal Studies.
J.Med.Chem., 68:4259-4286, 2025

PubMed Abstract: The BK channel, a large-conductance calcium-activated potassium channel, plays a crucial role in maintaining the homeostasis of the micturition cycle and airway-related functions. In this study, we optimized a novel BK channel activator, , with a diphenyl ether structure identified from library screening. This led to the discovery of potent activators, (EC = 0.12 μM, cell-based assay) and , an orally bioavailable derivative. Compound demonstrated potent efficacy in a spontaneous hypertensive rat (SHR) of urinary incontinence model, while compound showed dose-dependent cough suppression efficacy with an ED of 11.8 mg/kg in a citric acid-induced cough model. Furthermore, we reported the cryo-electron microscopy (cryo-EM) structures of the BK channel in complex with and at resolutions of 2.8 and 3.4 Å. Based on structural analyses, we determined the binding sites and key interaction residues of , which were validated via mutation studies.

PubMed: 39947888
DOI: 10.1021/acs.jmedchem.4c02008

実験手法

ELECTRON MICROSCOPY (2.8 Å)