The binding and mechanism of a positive allosteric modulator of Kv3 channels

Small-molecule modulators of diverse voltage-gated K + (Kv) channels may help treat a wide range of neurological disorders. However, developing effective modulators requires understanding of their mechanism of action. We apply an orthogonal approach to elucidate the mechanism of action of an imidazo...

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Published in:Nature communications 2024-03, Vol.15 (1), p.2533-2533, Article 2533
Main Authors: Liang, Qiansheng, Chi, Gamma, Cirqueira, Leonardo, Zhi, Lianteng, Marasco, Agostino, Pilati, Nadia, Gunthorpe, Martin J., Alvaro, Giuseppe, Large, Charles H., Sauer, David B., Treptow, Werner, Covarrubias, Manuel
Format: Article
Language:English
Subjects:
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Allosteric properties
Binding sites
Channel gating
Channels
Conformation
Epilepsy
Humanities and Social Sciences
Mental disorders
Modulation
Modulators
multidisciplinary
Neurological diseases
Neuromodulation
Neurosciences
Potassium channels (voltage-gated)
Science
Science (multidisciplinary)
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Summary:Small-molecule modulators of diverse voltage-gated K + (Kv) channels may help treat a wide range of neurological disorders. However, developing effective modulators requires understanding of their mechanism of action. We apply an orthogonal approach to elucidate the mechanism of action of an imidazolidinedione derivative (AUT5), a highly selective positive allosteric modulator of Kv3.1 and Kv3.2 channels. AUT5 modulation involves positive cooperativity and preferential stabilization of the open state. The cryo-EM structure of the Kv3.1/AUT5 complex at a resolution of 2.5 Å reveals four equivalent AUT5 binding sites at the extracellular inter-subunit interface between the voltage-sensing and pore domains of the channel’s tetrameric assembly. Furthermore, we show that the unique extracellular turret regions of Kv3.1 and Kv3.2 essentially govern the selective positive modulation by AUT5. High-resolution apo and bound structures of Kv3.1 demonstrate how AUT5 binding promotes turret rearrangements and interactions with the voltage-sensing domain to favor the open conformation. To promote the development of effective small molecule modulators that may help treat diverse neuropsychiatric disorders, this study elucidates the mechanism of a specific positive modulator of neuronal potassium channels at near-atomic resolution.
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-024-46813-8