7rnn

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Human ASIC1a-Nb.C1 complex

Structural highlights

7rnn is a 2 chain structure with sequence from Homo sapiens and Vicugna pacos. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Electron Microscopy, Resolution 2.86Å
Ligands:NAG
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

ASIC1_HUMAN Isoform 2 and isoform 3 function as proton-gated sodium channels; they are activated by a drop of the extracellular pH and then become rapidly desensitized. The channel generates a biphasic current with a fast inactivating and a slow sustained phase. Has high selectivity for sodium ions and can also transport lithium ions with high efficiency. Isoform 2 can also transport potassium, but with lower efficiency. It is nearly impermeable to the larger rubidium and cesium ions. Isoform 3 can also transport calcium ions. Mediates glutamate-independent Ca(2+) entry into neurons upon acidosis. This Ca(2+) overloading is toxic for cortical neurons and may be in part responsible for ischemic brain injury. Heteromeric channel assembly seems to modulate channel properties. Functions as a postsynaptic proton receptor that influences intracellular Ca(2+) concentration and calmodulin-dependent protein kinase II phosphorylation and thereby the density of dendritic spines. Modulates activity in the circuits underlying innate fear.[1] Isoform 1 does not display proton-gated cation channel activity.[2]

Publication Abstract from PubMed

ASIC1a is a proton-gated sodium channel involved in modulation of pain, fear, addiction, and ischemia-induced neuronal injury. We report isolation and characterization of alpaca-derived nanobodies (Nbs) that specifically target human ASIC1a. Cryo-electron microscopy of the human ASIC1a channel at pH 7.4 in complex with one of these, Nb.C1, yielded a structure at 2.9 A resolution. It is revealed that Nb.C1 binds to a site overlapping with that of the Texas coral snake toxin (MitTx1) and the black mamba venom Mambalgin-1; however, the Nb.C1-binding site does not overlap with that of the inhibitory tarantula toxin psalmotoxin-1 (PcTx1). Fusion of Nb.C1 with PcTx1 in a single polypeptide markedly enhances the potency of PcTx1, whereas competition of Nb.C1 and MitTx1 for binding reduces channel activation by the toxin. Thus, Nb.C1 is a molecular tool for biochemical and structural studies of hASIC1a; a potential antidote to the pain-inducing component of coral snake bite; and a candidate to potentiate PcTx1-mediated inhibition of hASIC1a in vivo for therapeutic applications.

Structure and analysis of nanobody binding to the human ASIC1a ion channel.,Wu Y, Chen Z, Sigworth FJ, Canessa CM Elife. 2021 Jul 28;10:e67115. doi: 10.7554/eLife.67115. PMID:34319232[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations
2 reviews cite this structure
Mechanisms of Action of the Peptide Toxins Targeting Human and Rodent Acid-Sensing Ion Channels and Relevance to Their In Vivo Analgesic Effects.
Verkest et al. (2022)
1 more
6 other articles
No citations found

See Also

References

  1. ↑ Dawson RJ, Benz J, Stohler P, Tetaz T, Joseph C, Huber S, Schmid G, Hugin D, Pflimlin P, Trube G, Rudolph MG, Hennig M, Ruf A. Structure of the Acid-sensing ion channel 1 in complex with the gating modifier Psalmotoxin 1. Nat Commun. 2012 Jul 3;3:936. doi: 10.1038/ncomms1917. PMID:22760635 doi:10.1038/ncomms1917
  2. ↑ Dawson RJ, Benz J, Stohler P, Tetaz T, Joseph C, Huber S, Schmid G, Hugin D, Pflimlin P, Trube G, Rudolph MG, Hennig M, Ruf A. Structure of the Acid-sensing ion channel 1 in complex with the gating modifier Psalmotoxin 1. Nat Commun. 2012 Jul 3;3:936. doi: 10.1038/ncomms1917. PMID:22760635 doi:10.1038/ncomms1917
  3. ↑ Wu Y, Chen Z, Sigworth FJ, Canessa CM. Structure and analysis of nanobody binding to the human ASIC1a ion channel. Elife. 2021 Jul 28;10:e67115. PMID:34319232 doi:10.7554/eLife.67115

Contents


PDB ID 7rnn

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OCA

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