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

Qiansheng Liang, Gamma Chi, Leonardo Cirqueira, Lianteng Zhi, Agostino Marasco, Nadia Pilati, Martin J. Gunthorpe, Giuseppe Alvaro, Charles H. Large, David B. Sauer, Werner Treptow and Manuel Covarrubias ()
Additional contact information
Qiansheng Liang: Sidney Kimmel Medical College of Thomas Jefferson University
Gamma Chi: University of Oxford, Roosevelt Drive
Leonardo Cirqueira: University of Brasilia
Lianteng Zhi: Sidney Kimmel Medical College of Thomas Jefferson University
Agostino Marasco: Via Corso Stati Uniti, 4f
Nadia Pilati: Via Corso Stati Uniti, 4f
Martin J. Gunthorpe: Ltd, Stevenage Bioscience Catalyst
Giuseppe Alvaro: Via Corso Stati Uniti, 4f
Charles H. Large: Ltd, Stevenage Bioscience Catalyst
David B. Sauer: University of Oxford, Roosevelt Drive
Werner Treptow: University of Brasilia
Manuel Covarrubias: Sidney Kimmel Medical College of Thomas Jefferson University

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-46813-8

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