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

Author

Listed:
  • Qiansheng Liang

    (Sidney Kimmel Medical College of Thomas Jefferson University
    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
    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
    Sidney Kimmel Medical College of Thomas Jefferson University)

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.

Suggested Citation

  • 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 & Manuel , 2024. "The binding and mechanism of a positive allosteric modulator of Kv3 channels," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46813-8
    DOI: 10.1038/s41467-024-46813-8
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    References listed on IDEAS

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