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TitleStructural insights into human acid-sensing ion channel 1a inhibition by snake toxin mambalgin1.
Journal, issue, pagesElife, Vol. 9, Year 2020
Publish dateSep 11, 2020
AuthorsDemeng Sun / Sanling Liu / Siyu Li / Mengge Zhang / Fan Yang / Ming Wen / Pan Shi / Tao Wang / Man Pan / Shenghai Chang / Xing Zhang / Longhua Zhang / Changlin Tian / Lei Liu /
PubMed AbstractAcid-sensing ion channels (ASICs) are proton-gated cation channels that are involved in diverse neuronal processes including pain sensing. The peptide toxin Mambalgin1 (Mamba1) from black mamba snake ...Acid-sensing ion channels (ASICs) are proton-gated cation channels that are involved in diverse neuronal processes including pain sensing. The peptide toxin Mambalgin1 (Mamba1) from black mamba snake venom can reversibly inhibit the conductance of ASICs, causing an analgesic effect. However, the detailed mechanism by which Mamba1 inhibits ASIC1s, especially how Mamba1 binding to the 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 the 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 preferentially binds hASIC1a in a closed state and reduces the proton sensitivity of the channel, representing a closed-state trapping mechanism.
External linksElife / PubMed:32915133 / PubMed Central
MethodsEM (single particle)
Resolution3.56 - 3.9 Å
Structure data

30346

7cfs

EMDB-30346, PDB-7cfs:
Cryo-EM strucutre of human acid-sensing ion channel 1a at pH 8.0
Method: EM (single particle) / Resolution: 3.56 Å

30347

7cft

EMDB-30347, PDB-7cft:
Cryo-EM strucutre of human acid-sensing ion channel 1a in complex with snake toxin Mambalgin1 at pH 8.0
Method: EM (single particle) / Resolution: 3.9 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

ChemComp-NA:
Unknown entry

Source
  • homo sapiens (human)
  • dendroaspis polylepis polylepis (black mamba)
KeywordsMEMBRANE PROTEIN / ASIC / human / resting state / cryo-EM structure / Mambalgin1 toxin

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