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From Proteopedia
Cryo-EM structure of Torpedo acetylcholine receptor in complex with alpha-bungarotoxin
Structural highlights
Function[ACHG_TETCF] After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane. [ACHA_TETCF] After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane. [ACHB_TETCF] After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane. [ACHD_TETCF] After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane. [3L21A_BUNMU] Binds with high affinity to muscular (tested on Torpedo marmorata, Kd=0.4 nM) and neuronal (tested on chimeric alpha-7/CHRNA7, Kd=0.95 nM) nicotinic acetylcholine receptor (nAChR) and inhibits acetylcholine from binding to the receptor, thereby impairing neuromuscular and neuronal transmission (PubMed:9305882). It also shows an activity on GABA(A) receptors (PubMed:16549768, PubMed:25634239). It antagonises GABA-activated currents with high potency when tested on primary hippocampal neurons (PubMed:25634239). It inhibits recombinantly expressed GABA(A) receptors composed of alpha-2-beta-2-gamma-2 (GABRA2-GABRB2-GABRG2) subunits with high potency (62.3% inhibition at 20 uM of toxin) (PubMed:25634239). It also shows a weaker inhibition on GABA(A) receptors composed of alpha-1-beta-2-gamma-2 (GABRA1-GABRB2-GABRG2) subunits, alpha-4-beta-2-gamma-2 (GABRA4-GABRB2-GABRG2) subunits, and alpha-5-beta-2-gamma-2 (GABRA5-GABRB2-GABRG2) subunits (PubMed:25634239). A very weak inhibition is also observed on GABA(A) receptor composed of alpha-1-beta-3-gamma-2 (GABRA1-GABRB3-GABRG2) (PubMed:26221036). It has also been shown to bind and inhibit recombinant GABA(A) receptor beta-3/GABRB3 subunit (Kd=about 50 nM) (PubMed:16549768). In addition, it blocks the extracellular increase of dopamine evoked by nicotine only at the higher dose (4.2 uM) (PubMed:9840221).[1] [2] [3] [4] Publication Abstract from PubMedThe nicotinic acetylcholine receptor, a pentameric ligand-gated ion channel, converts the free energy of binding of the neurotransmitter acetylcholine into opening of its central pore. Here we present the first high-resolution structure of the receptor type found in muscle-endplate membrane and in the muscle-derived electric tissues of fish. The native receptor was purified from Torpedo electric tissue and functionally reconstituted in lipids optimal for cryo-electron microscopy. The receptor was stabilized in a closed state by the binding of alpha-bungarotoxin. The structure reveals the binding of a toxin molecule at each of two subunit interfaces in a manner that would block the binding of acetylcholine. It also reveals a closed gate in the ion-conducting pore, formed by hydrophobic amino acid side chains, located approximately 60 A from the toxin binding sites. The structure provides a framework for understanding gating in ligand-gated channels and how mutations in the acetylcholine receptor cause congenital myasthenic syndromes. Structure of the Native Muscle-type Nicotinic Receptor and Inhibition by Snake Venom Toxins.,Rahman MM, Teng J, Worrell BT, Noviello CM, Lee M, Karlin A, Stowell MHB, Hibbs RE Neuron. 2020 Apr 2. pii: S0896-6273(20)30219-1. doi:, 10.1016/j.neuron.2020.03.012. PMID:32275860[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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