9ED1

Cryo-EM structure of the human KCa3.1/calmodulin channel in complex with Ca2+ and 1,4-dihydropyridine (DHP-103)

9ED1 の概要

• エントリーDOI: 10.2210/pdb9ed1/pdb
• EMDBエントリー: 47930
• 分子名称: Intermediate conductance calcium-activated potassium channel protein 4, Calmodulin-1, POTASSIUM ION, ... (4 entities in total)
• 機能のキーワード: ion channel, membrane protein, ca-binding protein, transport protein
• 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: 236694.97

構造登録者

Nam, Y.W.,Zhang, M. (登録日: 2024-11-15, 公開日: 2025-04-16, 最終更新日: 2025-05-07)

主引用文献

Ong, S.T.,Nam, Y.W.,Nasburg, J.A.,Ramanishka, A.,Ng, X.R.,Zhuang, Z.,Goay, S.S.M.,Nguyen, H.M.,Singh, L.,Singh, V.,Rivera, A.,Eyster, M.E.,Xu, Y.,Alper, S.L.,Wulff, H.,Zhang, M.,Chandy, K.G.
Design and structural basis of selective 1,4-dihydropyridine inhibitors of the calcium-activated potassium channel K Ca 3.1.
Proc.Natl.Acad.Sci.USA, 122:e2425494122-e2425494122, 2025

PubMed Abstract: The 1,4-dihydropyridines, drugs with well-established bioavailability and toxicity profiles, have proven efficacy in treating human hypertension, peripheral vascular disorders, and coronary artery disease. Every 1,4-dihydropyridine in clinical use blocks L-type voltage-gated calcium channels. We now report our development, using selective optimization of a side activity (SOSA), of a class of 1,4-dihydropyridines that selectively and potently inhibit the intermediate-conductance calcium-activated K channel K3.1, a validated therapeutic target for diseases affecting many organ systems. One of these 1,4-dihydropyridines, DHP-103, blocked K3.1 with an IC of 6 nM and exhibited exquisite selectivity over calcium channels and a panel of >100 additional molecular targets. Using high-resolution structure determination by cryogenic electron microscopy together with mutagenesis and electrophysiology, we delineated the drug binding pocket for DHP-103 within the water-filled central cavity of the K3.1 channel pore, where bound drug directly impedes ion permeation. DHP-103 inhibited gain-of-function mutant K3.1 channels that cause hereditary xerocytosis, suggesting its potential use as a therapeutic for this hemolytic anemia. In a rat model of acute ischemic stroke, the second leading cause of death worldwide, DHP-103 administered 12 h postischemic insult in proof-of-concept studies reduced infarct volume, improved balance beam performance (measure of proprioception) and decreased numbers of activated microglia in infarcted areas. K3.1-selective 1,4-dihydropyridines hold promise for the many diseases for which K3.1 has been experimentally confirmed as a therapeutic target.

PubMed: 40294255
DOI: 10.1073/pnas.2425494122

実験手法

ELECTRON MICROSCOPY (3.5 Å)