Structure of the Acid-sensing ion channel 1 in complex with the gating modifier Psalmotoxin 1

Abstract

Venom-derived peptide toxins can modify the gating characteristics of excitatory channels in neurons. How they bind and interfere with the fl ow of ions without directly blocking the ion permeation pathway remains elusive. Here we report the crystal structure of the trimeric chicken Acid-sensing ion channel 1 in complex with the highly selective gating modifi er Psalmotoxin 1 at 3.0 Å resolution. The structure reveals the molecular interactions of three toxin molecules binding at the proton-sensitive acidic pockets of Acid-sensing ion channel 1 and electron density consistent with a cation trapped in the central vestibule above the ion pathway. A hydrophobic patch and a basic cluster are the key structural elements of Psalmotoxin 1 binding, locking two separate regulatory regions in their relative, desensitized-like arrangement. Our results provide a general concept for gating modifi er toxin binding suggesting that both surface motifs are required to modify the gating characteristics of an ion channel.

Combination of Ambiguous and Unambiguous Data in the Restraint-driven Docking of Flexible Peptides with HADDOCK: The Binding of the Spider Toxin PcTx1 to the Acid Sensing Ion Channel (ASIC) 1a

“…25 Subsequently, the co-crystal structure of PcTx1 in complex with chicken ASIC1 (cASIC1) was published. 33,34 This confirmed the predicted location of the binding site and the fact that the structure of the binding site was largely unaffected by the presence of the peptide. Indeed, the root mean squared deviation (RMSD) between all residues within 10 Å of the peptide in the complex and those in the apo structure was < 1 Å.…”

“…The residues used to form AIRs and UDRs were based on 8 peptide and 24 channel residues that were observed to form peptide-channel contacts within the PcTx1-cASIC1 crystal structure interface. 34 These are listed in Table S1 and S2 in the supporting information. Residues for AIRs were randomly selected from these peptide and channel residues and in the case of the UDRs from the corresponding 37 pairwise peptide-channel contacts.…”

“…The first consisted of the structures of the channel and the peptide extracted from the co-crystal structure (PDB 3S3X). 34 In this case there is an exact conformational match between the structure of the peptide and the binding pocket in the channel. These runs are labelled C X P X where the subscript X refers to X-ray.…”

“…For the C X P X experiments the structures of the channel and the peptide from the crystal structure of the PcTx1-cASIC1 complex (PDB 3S3X) 34 were used. The three subunits forming the channel (chains A, B and C) and one toxin (chain E) were extracted while crystallographic water, glucosamine molecules and ions were removed.…”

An efficient transcriptome analysis pipeline to accelerate venom peptide discovery and characterisation

“…Toxins have also been used to probe receptor-ligand interactions at their respective molecular targets. For example, the crystal structure of ASIC1a bound to psalmotoxin-1 (Baconguis and Gouaux, 2012;Dawson et al, 2012) isolated from the spider Araneae theraphosidae (Escoubas et al, 2000) was used to map the toxin-binding domain and understand activation mechanisms of ASICs (Baconguis and Gouaux, 2012). The co-crystallisation of ASIC1a with MitTx, a pain causing Texas coral snake toxin revealed the open state conformation of the channel (Baconguis et al, 2014).…”