5AFK

alpha7-AChBP in complex with lobeline and fragment 2

5AFK の概要

• エントリーDOI: 10.2210/pdb5afk/pdb
• 関連するPDBエントリー: 5AFH 5AFJ 5AFL 5AFM 5AFN
• 分子名称: ACETYLCHOLINE-BINDING PROTEIN, NEURONAL ACETYLCHOLINE RECEPTOR SUBUNIT ALPHA-7, alpha-D-mannopyranose-(1-3)-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, ... (7 entities in total)
• 機能のキーワード: transport protein, pentameric ligand-gated ion channels, cys-loop receptor, nicotinic acetylcholine receptor, allosteric modulation, drug discovery
• 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: 124440.57

構造登録者

Spurny, R.,Debaveye, S.,Farinha, A.,Veys, K.,Gossas, T.,Atack, J.,Bertrand, D.,Kemp, J.,Vos, A.,Danielson, U.H.,Tresadern, G.,Ulens, C. (登録日: 2015-01-22, 公開日: 2015-05-06, 最終更新日: 2020-07-29)

主引用文献

Spurny, R.,Debaveye, S.,Farinha, A.,Veys, K.,Vos, A.M.,Gossas, T.,Atack, J.,Bertrand, S.,Bertrand, D.,Danielson, U.H.,Tresadern, G.,Ulens, C.
Molecular Blueprint of Allosteric Binding Sites in a Homologue of the Agonist-Binding Domain of the Alpha7 Nicotinic Acetylcholine Receptor.
Proc.Natl.Acad.Sci.USA, 112:E2543-, 2015

PubMed Abstract: The α7 nicotinic acetylcholine receptor (nAChR) belongs to the family of pentameric ligand-gated ion channels and is involved in fast synaptic signaling. In this study, we take advantage of a recently identified chimera of the extracellular domain of the native α7 nicotinic acetylcholine receptor and acetylcholine binding protein, termed α7-AChBP. This chimeric receptor was used to conduct an innovative fragment-library screening in combination with X-ray crystallography to identify allosteric binding sites. One allosteric site is surface-exposed and is located near the N-terminal α-helix of the extracellular domain. Ligand binding at this site causes a conformational change of the α-helix as the fragment wedges between the α-helix and a loop homologous to the main immunogenic region of the muscle α1 subunit. A second site is located in the vestibule of the receptor, in a preexisting intrasubunit pocket opposite the agonist binding site and corresponds to a previously identified site involved in positive allosteric modulation of the bacterial homolog ELIC. A third site is located at a pocket right below the agonist binding site. Using electrophysiological recordings on the human α7 nAChR we demonstrate that the identified fragments, which bind at these sites, can modulate receptor activation. This work presents a structural framework for different allosteric binding sites in the α7 nAChR and paves the way for future development of novel allosteric modulators with therapeutic potential.

PubMed: 25918415
DOI: 10.1073/PNAS.1418289112

実験手法

X-RAY DIFFRACTION (2.381 Å)