6HY7

Crystal structure of alpha9 nAChR extracellular domain in complex with alpha-conotoxin RgIA

Summary for 6HY7

• Entry DOI: 10.2210/pdb6hy7/pdb
• Descriptor: Neuronal acetylcholine receptor subunit alpha-9, Alpha-conotoxin RgIA, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (5 entities in total)
• Functional Keywords: alpha9, ion channel, nachr, acetylcholine, conotoxin, rgia, antagonist, toxin
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 27389.40

Authors

Giastas, P.,Zouridakis, M. (deposition date: 2018-10-19, release date: 2019-05-22, Last modification date: 2024-01-24)

Primary citation

Zouridakis, M.,Papakyriakou, A.,Ivanov, I.A.,Kasheverov, I.E.,Tsetlin, V.,Tzartos, S.,Giastas, P.
Crystal Structure of the Monomeric Extracellular Domain of alpha 9 Nicotinic Receptor Subunit in Complex With alpha-Conotoxin RgIA: Molecular Dynamics Insights Into RgIA Binding to alpha 9 alpha 10 Nicotinic Receptors.
Front Pharmacol, 10:474-474, 2019

PubMed Abstract: The α9 subunit of nicotinic acetylcholine receptors (nAChRs) exists mainly in heteropentameric assemblies with α10. Accumulating data indicate the presence of three different binding sites in α9α10 nAChRs: the α9(+)/α9(-), the α9(+)/α10(-), and the α10(+)/α9(-). The major role of the principal (+) side of the extracellular domain (ECD) of α9 subunit in binding of the antagonists methyllylcaconitine and α-bungarotoxin was shown previously by the crystal structures of the monomeric α9-ECD with these molecules. Here we present the 2.26-Å resolution crystal structure of α9-ECD in complex with α-conotoxin (α-Ctx) RgIA, a potential drug for chronic pain, the first structure reported for a complex between an nAChR domain and an α-Ctx. Superposition of this structure with those of other α-Ctxs bound to the homologous pentameric acetylcholine binding proteins revealed significant similarities in the orientation of bound conotoxins, despite the monomeric state of the α9-ECD. In addition, ligand-binding studies calculated a binding affinity of RgIA to the α9-ECD at the low micromolar range. Given the high identity between α9 and α10 ECDs, particularly at their (+) sides, the presented structure was used as template for molecular dynamics simulations of the ECDs of the human α9α10 nAChR in pentameric assemblies. Our results support a favorable binding of RgIA at α9(+)/α9(-) or α10(+)/α9(-) rather than the α9(+)/α10(-) interface, in accordance with previous mutational and functional data.

PubMed: 31118896
DOI: 10.3389/fphar.2019.00474

Experimental method

X-RAY DIFFRACTION (2.26 Å)