5OUI

Humanized alpha-AChBP (acetylcholine binding protein) in complex with allosteric binder fragment CU2017

5OUI の概要

• エントリーDOI: 10.2210/pdb5oui/pdb
• 関連するPDBエントリー: 5afm
• 分子名称: Acetylcholine binding protein, alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (8 entities in total)
• 機能のキーワード: acetylcholine binding protein, nicotinic acetylcholine receptor, choline-binding protein
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 124177.17

構造登録者

Delbart, F.,Gruss, F.,Ulens, C. (登録日: 2017-08-23, 公開日: 2017-11-29, 最終更新日: 2024-11-06)

主引用文献

Delbart, F.,Brams, M.,Gruss, F.,Noppen, S.,Peigneur, S.,Boland, S.,Chaltin, P.,Brandao-Neto, J.,von Delft, F.,Touw, W.G.,Joosten, R.P.,Liekens, S.,Tytgat, J.,Ulens, C.
An allosteric binding site of the alpha 7 nicotinic acetylcholine receptor revealed in a humanized acetylcholine-binding protein.
J. Biol. Chem., 293:2534-2545, 2018

PubMed Abstract: Nicotinic acetylcholine receptors (nAChRs) belong to the family of pentameric ligand-gated ion channels and mediate fast excitatory transmission in the central and peripheral nervous systems. Among the different existing receptor subtypes, the homomeric α7 nAChR has attracted considerable attention because of its possible implication in several neurological and psychiatric disorders, including cognitive decline associated with Alzheimer's disease or schizophrenia. Allosteric modulators of ligand-gated ion channels are of particular interest as therapeutic agents, as they modulate receptor activity without affecting normal fluctuations of synaptic neurotransmitter release. Here, we used X-ray crystallography and surface plasmon resonance spectroscopy of α7-acetylcholine-binding protein (AChBP), a humanized chimera of a snail AChBP, which has 71% sequence similarity with the extracellular ligand-binding domain of the human α7 nAChR, to investigate the structural determinants of allosteric modulation. We extended previous observations that an allosteric site located in the vestibule of the receptor offers an attractive target for receptor modulation. We introduced seven additional humanizing mutations in the vestibule-located binding site of AChBP to improve its suitability as a model for studying allosteric binding. Using a fragment-based screening approach, we uncovered an allosteric binding site located near the β8-β9 loop, which critically contributes to coupling ligand binding to channel opening in human α7 nAChR. This work expands our understanding of the topology of allosteric binding sites in AChBP and, by extrapolation, in the human α7 nAChR as determined by electrophysiology measurements. Our insights pave the way for drug design strategies targeting nAChRs involved in ion channel-mediated disorders.

PubMed: 29237730
DOI: 10.1074/jbc.M117.815316

実験手法

X-RAY DIFFRACTION (3.1 Å)