A mechanism for the activation of the mechanosensitive Piezo1 channel by the small molecule Yoda1

• Published in: Nature communications 2019-10, Vol.10 (1), p.4503-10, Article 4503
• Main Authors: Botello-Smith, Wesley M., Jiang, Wenjuan, Zhang, Han, Ozkan, Alper D., Lin, Yi-Chun, Pham, Christine N., Lacroix, Jérôme J., Luo, Yun
• Format: Article
• Language: English
• Subjects: 119/118; 14; 631/154/436/2387; 631/57/2266; 631/92/269; 9/74; Activation; Agonists; Allosteric properties; Binding Sites; Biological activity; Calcium; Calcium imaging; Calcium signalling; Channels; Computer simulation; Electrophysiology; HEK293 Cells; Humanities and Social Sciences; Humans; Intravital Microscopy - methods; Ion Channel Gating - drug effects; Ion Channels - agonists; Ion Channels - genetics; Ion Channels - metabolism; Ligands; Modulators; Molecular dynamics; Molecular Dynamics Simulation; multidisciplinary; Mutation; Optical Imaging - methods; Patch-Clamp Techniques; Protein Binding; Protein Domains; Pyrazines - pharmacology; Science; Science (multidisciplinary); Signal processing; Thiadiazoles - pharmacology; Vertebrates
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-12501-1

Mechanosensitive Piezo1 and Piezo2 channels transduce various forms of mechanical forces into cellular signals that play vital roles in many important biological processes in vertebrate organisms. Besides mechanical forces, Piezo1 is selectively activated by micromolar concentrations of the small molecule Yoda1 through an unknown mechanism. Here, using a combination of all-atom molecular dynamics simulations, calcium imaging and electrophysiology, we identify an allosteric Yoda1 binding pocket located in the putative mechanosensory domain, approximately 40 Å away from the central pore. Our simulations further indicate that the presence of the agonist correlates with increased tension-induced motions of the Yoda1-bound subunit. Our results suggest a model wherein Yoda1 acts as a molecular wedge, facilitating force-induced conformational changes, effectively lowering the channel’s mechanical threshold for activation. The identification of an allosteric agonist binding site in Piezo1 channels will pave the way for the rational design of future Piezo modulators with clinical value. Besides mechanical forces, the mechanosensitive channel Piezo1 is activated by the small molecule Yoda1 through an unknown mechanism. Here, using molecular dynamics simulations, calcium imaging and electrophysiology, the authors identify an allosteric Yoda1 binding pocket located in the putative mechanosensory domain.