Acid-sensing ion channels (ASICs) are proton-gated cation channels that are involved in diverse neuronal processes including pain sensing. Peptide toxin Mambalgin1 (Mamba1) from black mamba snake venom can reversibly inhibit the conductance of ASICs, showing an analgesic effect. However, the detailed inhibitory mechanism of Mamba1 on ASIC1s, especially how Mamba1 binding to extracellular domain affects the conformational changes of the transmembrane domain of ASICs remains elusive. Here, we present single-particle cryo-EM structures of human ASIC1a (hASIC1a) and hASIC1a-Mamba1 complex at resolutions of 3.56 and 3.90 Å, respectively. The structures revealed the inhibited conformation of hASIC1a upon Mamba1 binding. The combination of the structural and physiological data indicates that Mamba1 prefers to bind hASIC1a in a closed state and reduces the proton sensitivity of the channel, representing a closed-state trapping mechanism.
The EM maps for hASIC1a and hASIC1a-Mamba1 complex have been deposited in EMDB (www.ebi.ac.uk/pdbe/emdb/) with accession codes EMD-30346 and EMD-30347. The atomic coordinates for hASIC1a and hASIC1a-Mamba1 complex have been deposited in the Protein Data Bank (www.rcsb.org) with accession codes 7CFS and 7CFT respectively
Identification of a calcium permeable human acid-sensing ion channel 1 transcript variantNCBI GenBank: HM991481.1.
- Changlin Tian
- Changlin Tian
- Lei Liu
- Demeng Sun
- Lei Liu
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
- Leon D Islas, Universidad Nacional Autónoma de México, Mexico
© 2020, Tian et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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