ArticleBritish journal of pharmacology2015
Molecular dynamics and functional studies define a hot spot of crystal contacts essential for PcTx1 inhibition of acid-sensing ion channel 1a.
Article in British journal of pharmacology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 43 citations in OpenAlex.
- The Isolated Thumb Domain of Acid-Sensing Ion Channels Forms a Minimal Folding Unit Enabling Ligand Binding Studies.Angewandte Chemie (International ed. in English) · 2026Article
- Mechanism of acid-sensing ion channel modulation by Hi1a.The Journal of general physiology · 2024Article
- Mutagenesis of the Peptide Inhibitor of ASIC3 Channel Introduces Binding to Thumb Domain of ASIC1a but Reduces Analgesic Activity.Marine drugs · 2024Article
- Review
- Article
- High-throughput characterization of photocrosslinker-bearing ion channel variants to map residues critical for function and pharmacology.PLoS biology · 2021Article
- Animal toxins - Nature's evolutionary-refined toolkit for basic research and drug discovery.Biochemical pharmacology · 2020Review
- APETx-Like Peptides from the Sea AnemoneToxins · 2020Article
- Mechanism and site of action of big dynorphin on ASIC1a.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Interactions between Curcumin Derivatives and Amyloid-β Fibrils: Insights from Molecular Dynamics Simulations.Journal of chemical information and modeling · 2020Article
- Animal, Herb, and Microbial Toxins for Structural and Pharmacological Study of Acid-Sensing Ion Channels.Frontiers in pharmacology · 2020Review
- Mimicking Strategy for Protein-Protein Interaction Inhibitor Discovery by Virtual Screening.Molecules (Basel, Switzerland) · 2019Review
- Mutations in the palm domain disrupt modulation of acid-sensing ion channel 1a currents by neuropeptides.Scientific reports · 2019Article
- Retracted Article: ASIC1a involves acidic microenvironment-induced activation and autophagy of pancreatic stellate cells.RSC advances · 2018Article
- An overview of recent molecular dynamics applications as medicinal chemistry tools for the undruggable site challenge.MedChemComm · 2018Review
- Anticancer, antimicrobial, and analgesic activities of spider venoms.Toxicology research · 2018Review
- Potent neuroprotection after stroke afforded by a double-knot spider-venom peptide that inhibits acid-sensing ion channel 1a.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Molecular Simulations of Disulfide-Rich Venom Peptides with Ion Channels and Membranes.Molecules (Basel, Switzerland) · 2017Review
- Mambalgin-1 Pain-relieving Peptide, Stepwise Solid-phase Synthesis, Crystal Structure, and Functional Domain for Acid-sensing Ion Channel 1a Inhibition.The Journal of biological chemistry · 2016Article
- Selective inhibition of ASIC1a confers functional and morphological neuroprotection following traumatic spinal cord injury.F1000Research · 2016Article
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
background and purposeThe spider-venom peptide PcTx1 is the most potent and selective inhibitor of acid-sensing ion channel (ASIC) 1a. It has centrally acting analgesic activity and is neuroprotective in rodent models of ischaemic stroke. Understanding the molecular details of the PcTx1 : ASIC1a interaction should facilitate development of therapeutically useful ASIC1a modulators. Previously, we showed that several key pharmacophore residues of PcTx1 reside in a dynamic β-hairpin loop; conclusions confirmed by recent crystal structures of the complex formed between PcTx1 and chicken ASIC1 (cASIC1). Numerous peptide : channel contacts were observed in these crystal structures, but it remains unclear which of these are functionally important. EXPERIMENTAL APPROACH: We combined molecular dynamics (MD) simulations of the PcTx1 : cASIC1 complex with mutagenesis of PcTx1 and rat ASIC1a. KEY
resultsCrystal structures of the PcTx1 : cASIC1 complex indicated that 15 PcTx1 residues form a total of 57 pairwise intermolecular contacts (<5 Å) with 32 channel residues. MD simulations, however, suggested that about half of these interactions do not persist in solution. Mutation to alanine of only eight of 15 PcTx1 contact residues substantially altered ASIC1a inhibition by PcTx1. Our data reveal that many of the peptide-channel interactions observed in the PcTx1 : cASIC1 crystal structures are not important for PcTx1 inhibition of rat ASIC1a. CONCLUSIONS AND IMPLICATIONS: We identified the atomic interactions that are critical for PcTx1 inhibition of ASIC1a. Our data highlight the value of combining structural information, MD and functional experiments to obtain detailed insight into the molecular basis of protein : protein interactions.
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