2PGZ

Crystal structure of Cocaine bound to an ACh-Binding Protein

2PGZ の概要

• エントリーDOI: 10.2210/pdb2pgz/pdb
• 分子名称: Soluble acetylcholine receptor, 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, COCAINE, ... (6 entities in total)
• 機能のキーワード: non-competitive inhibitors, nicotinic acetycholine receptors, acetycholine-binding protein, benzodiazepine, galanthamine, cocaine, choline binding protein, choline-binding protein
• 由来する生物種: Aplysia californica (California sea hare)
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 133381.94

構造登録者

Hansen, S.B.,Taylor, P. (登録日: 2007-04-10, 公開日: 2007-07-03, 最終更新日: 2024-10-09)

主引用文献

Hansen, S.B.,Taylor, P.
Galanthamine and non-competitive inhibitor binding to ACh-binding protein: evidence for a binding site on non-alpha-subunit interfaces of heteromeric neuronal nicotinic receptors.
J.Mol.Biol., 369:895-901, 2007

PubMed Abstract: Rapid neurotransmission is mediated through a superfamily of Cys-loop receptors that includes the nicotinic acetylcholine (nAChR), gamma-aminobutyric acid (GABA(A)), serotonin (5-HT(3)) and glycine receptors. A class of ligands, including galanthamine, local anesthetics and certain toxins, interact with nAChRs non-competitively. Suggested modes of action include blockade of the ion channel, modulation from undefined extracellular sites, stabilization of desensitized states, and association with annular or boundary lipid. Alignment of mammalian Cys-loop receptors shows aromatic residues, found in the acetylcholine or ligand-binding pocket of nAChRs, are conserved in all subunit interfaces of neuronal nAChRs, including those that are not formed by alpha subunits on the principal side of the transmitter binding site. The amino-terminal domain containing the ligand recognition site is homologous to the soluble acetylcholine-binding protein (AChBP) from mollusks, an established structural and functional surrogate. We assess ligand specificity and employ X-ray crystallography with AChBP to demonstrate ligand interactions at subunit interfaces lacking vicinal cysteines (i.e. the non-alpha subunit interfaces in nAChRs). Non-competitive nicotinic ligands bind AChBP with high affinity (K(d) 0.015-6 microM). We mutated the vicinal cysteine residues in loop C of AChBP to mimic the non-alpha subunit interfaces of neuronal nAChRs and other Cys loop receptors. Classical nicotinic agonists show a 10-40-fold reduction in binding affinity, whereas binding of ligands known to be non-competitive are not affected. X-ray structures of cocaine and galanthamine bound to AChBP (1.8 A and 2.9 A resolution, respectively) reveal interactions deep within the subunit interface and the absence of a contact surface with the tip of loop C. Hence, in addition to channel blocking, non-competitive interactions with heteromeric neuronal nAChR appear to occur at the non-alpha subunit interface, a site presumed to be similar to that of modulating benzodiazepines on GABA(A) receptors.

PubMed: 17481657
DOI: 10.1016/j.jmb.2007.03.067

実験手法

X-RAY DIFFRACTION (1.76 Å)