Human acid-sensing ion channel 1a inhibition by snake toxin Mambalgin1

September 27, 2020

During the process of natural selection and evolution, many animals and plants, such as snakes, scorpions and sea anemones, have acquired the ability to produce venom, which is regarded as their strong weapon for self-defense and predation. Toxic peptides extracted from venom can specifically plays a key role in Acid-Sensing Ion Channel (ASIC), cell membrane surface receptors and proteins intensively involved in life activities. The interactions between venom and target proteins present the advantages of high specification and high affinity, in which venom has been treated as molecular tools to research in protein structures and their physiological functions for drug development.

On September 11th, 2020, a research group from University of Science and Technology of China, led by TIAN Changlin, in cooperation with LIU Lei's research group from Tsinghua University, initially resolved the hASIC1a and freeze electron structure of the compound of hASCI1a and Mambalgin1 through freeze electron microscopic technology. Also, the two research groups applied 19F-NMR and electrophysiological function analysis of patch clamp into use, uncovering the structural mechanism of polypeptide combination and hASIC1a inhibition. This result has been published on eLife with the title of "Structural Insights into Human Acid-sensing Ion Channel 1a Inhibition by Snake Toxin Mambalgin1".

In 2014, Tian Changlin Lab successfully produced Mambagin 1 venom and resolved its solution structure by NMR methods. However, it was still in question that how Mambalgin could specifically recognize and inhibit the mechanism of activity in human ASIC.

The compound structure of hASC1a/mambalgin1 shows that this kind of venom polypeptides are bonded to the outward of hASIC1a through electrostatic and hydrophobic interaction, having revised the former hypothesis of interaction between venom and ASIC. Further studies showed that Mambalgin1 selectively bonded closed ASCI and locked it in closed conformation. Even the concentration of protons elevates, ASIC can hardly switch to the open state. Therefore, the author put forwarded the concept of "closed-state trapping" mechanism, where Mambalgin1 could achieve ASIC activity inhibition. This would prepare the foundation for polypeptide medicine development.

University of Science and Technology of China

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