5J5I

X-Ray Crystal Structure of Acetylcholine Binding Protein (AChBP) in Complex with 4-(2-amino-6-{bis[(pyridin-2-yl)methyl]amino}pyrimidin-4-yl)phenol

5J5I の概要

• エントリーDOI: 10.2210/pdb5j5i/pdb
• 関連するPDBエントリー: 4QAA 4QAB 4QAC 5J5F 5J5G 5J5H
• 分子名称: Acetylcholine-binding protein, 2-acetamido-2-deoxy-beta-D-glucopyranose, 4-(2-amino-6-{bis[(pyridin-2-yl)methyl]amino}pyrimidin-4-yl)phenol, ... (5 entities in total)
• 機能のキーワード: acetylcholine-binding protein, achbp
• 由来する生物種: Lymnaea stagnalis (Great pond snail)
• 細胞内の位置: Secreted: P58154
• タンパク質・核酸の鎖数: 10
• 化学式量合計: 256645.77

構造登録者

Kaczanowska, K.,Harel, M.,Camacho Hernandez, G.A.,Taylor, P. (登録日: 2016-04-02, 公開日: 2017-03-08, 最終更新日: 2024-10-23)

主引用文献

Kaczanowska, K.,Camacho Hernandez, G.A.,Bendiks, L.,Kohs, L.,Cornejo-Bravo, J.M.,Harel, M.,Finn, M.G.,Taylor, P.
Substituted 2-Aminopyrimidines Selective for alpha 7-Nicotinic Acetylcholine Receptor Activation and Association with Acetylcholine Binding Proteins.
J. Am. Chem. Soc., 139:3676-3684, 2017

PubMed Abstract: Through studies with ligand binding to the acetylcholine binding protein (AChBP), we previously identified a series of 4,6-substituted 2-aminopyrimidines that associate with this soluble surrogate of the nicotinic acetylcholine receptor (nAChR) in a cooperative fashion, not seen for classical nicotinic agonists and antagonists. To examine receptor interactions of this structural family on ligand-gated ion channels, we employed HEK cells transfected with cDNAs encoding three requisite receptor subtypes: α7-nAChR, α4β2-nAChR, and a serotonin receptor (5-HTR), along with a fluorescent reporter. Initial screening of a series of over 50 newly characterized 2-aminopyrimidines with affinity for AChBP showed only two to be agonists on the α7-nAChR below 10 μM concentration. Their unique structural features were incorporated into design of a second subset of 2-aminopyrimidines yielding several congeners that elicited α7 activation with EC values of 70 nM and K values for AChBP in a similar range. Several compounds within this series exhibit specificity for the α7-nAChR, showing no activation or antagonism of α4β2-nAChR or 5-HT3AR at concentrations up to 10 μM, while others were weaker antagonists (or partial agonists) on these receptors. Analysis following cocrystallization of four ligand complexes with AChBP show binding at the subunit interface, but with an orientation or binding pose that differs from classical nicotinic agonists and antagonists and from the previously analyzed set of 2-aminopyrimidines that displayed distinct cooperative interactions with AChBP. Orientations of aromatic side chains of these complexes are distinctive, suggesting new modes of binding at the agonist-antagonist site and perhaps an allosteric action for heteromeric nAChRs.

PubMed: 28221788
DOI: 10.1021/jacs.6b10746

実験手法

X-RAY DIFFRACTION (2.326 Å)