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Structural and thermodynamic framework for PIEZO1 modulation by small molecules.
Wenjuan Jiang1, Tharaka D Wijerathne2, Han Zhang3,4,5,6
1Department of Biotechnology and Pharmaceutical Sciences, Western University of Health Sciences, Pomona, CA 91766.
Summary
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.
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.
