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Mechanically-gated Ion Channels

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Mechanically-gated ion channels are proteins found in eukaryotic and prokaryotic cell membranes that open in response to mechanical stress. Tension, compression, swelling, and shear stress can alter the conformation of the protein, opening a transmembrane channel that allows the passage of ions for signal transmission. In eukaryotes, mechanically-gated channels are distributed in several regions like the neurons, lungs, skin, bladder, and heart, where they play critical roles in numerous...

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Updated: Jul 9, 2025

One-channel Cell-attached Patch-clamp Recording

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Structural and thermodynamic framework for PIEZO1 modulation by small molecules.

Wenjuan Jiang¹, Tharaka D Wijerathne², Han Zhang^3,4,5,6

¹Department of Biotechnology and Pharmaceutical Sciences, Western University of Health Sciences, Pomona, CA 91766.

Proceedings of the National Academy of Sciences of the United States of America

|December 7, 2023

Summary

This summary is machine-generated.

Yoda1 activates PIEZO1 channels by disrupting contacts between repeats A and B. This study reveals a deeper binding site and identifies new PIEZO1 agonists, aiding rational drug design for mechanosensitive channels.

Keywords:

PIEZO1 Yoda1 agonist efficacy alchemical free energy calculations mechanosensitive channel

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Last Updated: Jul 9, 2025

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Published on: July 3, 2018

Area of Science:

Biophysics
Pharmacology
Molecular Biology

Background:

Mechanosensitive PIEZO channels are key drug targets.
Yoda1 is a known PIEZO1 activator, but its mechanism is unclear.
Understanding PIEZO1 modulation is crucial for therapeutic development.

Purpose of the Study:

Elucidate the molecular mechanism of Yoda1 activation of PIEZO1 channels.
Identify novel PIEZO1 modulators through computational screening.
Provide a structural and thermodynamic basis for rational PIEZO1 drug design.

Main Methods:

Disulfide cross-linking to probe PIEZO1 repeat interactions.
Molecular dynamics simulations (absolute and relative binding free energy).
Virtual screening of a large compound library using fragment maps.

Main Results:

Yoda1's effect is redox-dependent, linked to PIEZO1 repeats A and B.
Yoda1 binds with higher affinity to an open-state PIEZO1 conformation.
Simulations recapitulated structure-activity relationships of Yoda1 analogs.
Identified two novel chemical scaffolds as PIEZO1 agonists.

Conclusions:

Yoda1 activates PIEZO1 by wedging apart repeats A and B.
A detailed thermodynamic and structural framework for PIEZO1 modulation is established.
Computational methods show promise for discovering modulators of membrane proteins.