Structural Insights into Human Acid-sensing Ion Channel 1a Inhibition by Snake Toxin Mambalgin1
- University of Science and Tehnology of China, China
- University of Science and Technology of China, China
- Chinese Academy of Sciences, China
- Tsinghua University, China
- Zhejiang University, China
Abstract
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.
Data availability
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
Article and author information
Author details
Funding
Ministry of Science and Technology of the People's Republic of China (National Key Research and Development Project,2017YFA0505201,2017YFA0505403 and 2016YFA0400903)
- Changlin Tian
Chinese Academy of Sciences (Queensland-Chinese Academy of Sciences (Q-CAS) Collaborative Science Fund,GJHZ201946)
- Changlin Tian
Ministry of Science and Technology of the People's Republic of China (National Key Research and Development Project,2017YFA0505200)
- Lei Liu
National Natural Science Foundation of China (31600601,21778051)
- Demeng Sun
National Natural Science Foundation of China (91753205,21532004)
- Lei Liu
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Leon D Islas, Universidad Nacional Autónoma de México, Mexico
Version history
- Received: March 20, 2020
- Accepted: September 10, 2020
- Accepted Manuscript published: September 11, 2020 (version 1)
- Version of Record published: October 13, 2020 (version 2)
Copyright
© 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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Structural Insights into Human Acid-sensing Ion Channel 1a Inhibition by Snake Toxin Mambalgin1
eLife 9:e57096.
https://doi.org/10.7554/eLife.57096
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