6hy7
From Proteopedia
Crystal structure of alpha9 nAChR extracellular domain in complex with alpha-conotoxin RgIA
Structural highlights
FunctionACHA9_HUMAN Ionotropic receptor with a probable role in the modulation of auditory stimuli. Agonist binding may induce an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane. The channel is permeable to a range of divalent cations including calcium, the influx of which may activate a potassium current which hyperpolarizes the cell membrane. In the ear, this may lead to a reduction in basilar membrane motion, altering the activity of auditory nerve fibers and reducing the range of dynamic hearing. This may protect against acoustic trauma. May also regulate keratinocyte adhesion.[1] [2] Publication Abstract from PubMedThe alpha9 subunit of nicotinic acetylcholine receptors (nAChRs) exists mainly in heteropentameric assemblies with alpha10. Accumulating data indicate the presence of three different binding sites in alpha9alpha10 nAChRs: the alpha9(+)/alpha9(-), the alpha9(+)/alpha10(-), and the alpha10(+)/alpha9(-). The major role of the principal (+) side of the extracellular domain (ECD) of alpha9 subunit in binding of the antagonists methyllylcaconitine and alpha-bungarotoxin was shown previously by the crystal structures of the monomeric alpha9-ECD with these molecules. Here we present the 2.26-A resolution crystal structure of alpha9-ECD in complex with alpha-conotoxin (alpha-Ctx) RgIA, a potential drug for chronic pain, the first structure reported for a complex between an nAChR domain and an alpha-Ctx. Superposition of this structure with those of other alpha-Ctxs bound to the homologous pentameric acetylcholine binding proteins revealed significant similarities in the orientation of bound conotoxins, despite the monomeric state of the alpha9-ECD. In addition, ligand-binding studies calculated a binding affinity of RgIA to the alpha9-ECD at the low micromolar range. Given the high identity between alpha9 and alpha10 ECDs, particularly at their (+) sides, the presented structure was used as template for molecular dynamics simulations of the ECDs of the human alpha9alpha10 nAChR in pentameric assemblies. Our results support a favorable binding of RgIA at alpha9(+)/alpha9(-) or alpha10(+)/alpha9(-) rather than the alpha9(+)/alpha10(-) interface, in accordance with previous mutational and functional data. Crystal Structure of the Monomeric Extracellular Domain of alpha9 Nicotinic Receptor Subunit in Complex With alpha-Conotoxin RgIA: Molecular Dynamics Insights Into RgIA Binding to alpha9alpha10 Nicotinic Receptors.,Zouridakis M, Papakyriakou A, Ivanov IA, Kasheverov IE, Tsetlin V, Tzartos S, Giastas P Front Pharmacol. 2019 May 1;10:474. doi: 10.3389/fphar.2019.00474. eCollection, 2019. PMID:31118896[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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