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PreprintCC BYbioRxiv

Mechanistical and structural basis of Kv channel inhibition by 4 aminopyridine

  • B. I. Pinto-Anwandter
  • R. Agrawal
  • T. Thomas
  • E. Perozo
  • B. Roux
  • F. Bezanilla1
  1. 1University of Chicago
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Abstract

Inhibition of Kv channels by 4-aminopyridine (4AP) improves motor function in multiple sclerosis by enhancing neuronal excitability. The mechanism of inhibition and the structural basis of 4AP binding to Kv channels remain unclear. Here, we determined the structure of the Shaker V369I-I372L-S376T (ILT) mutant bound to 4AP at 3.3 [A], demonstrating that 4AP binds to the closed state of the channel. This structure is inconsistent with an open channel block mechanism. Electrophysiology experiments show that 4AP binds even when intracellular pore access is constitutively blocked, suggesting that 4AP enters the pore through membrane-facing fenestrations. MD simulations and mutational analysis agree with the proposed fenestration pathway and suggest that 4AP binds in its neutral form. These results support a mechanism where 4AP binds to a partially activated closed state that prevents complete activation of Kv channels, explaining its pharmacological activity.

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Cite

BibTeXRIS
BibTeX
@misc{pintoanwandter2026mechanistical,
  title = {{Mechanistical and structural basis of Kv channel inhibition by 4 aminopyridine}},
  author = {B. I. Pinto-Anwandter and R. Agrawal and T. Thomas and E. Perozo and B. Roux and F. Bezanilla},
  howpublished = {bioRxiv},
  year = {2026},
  month = sep,
  doi = {10.64898/2026.09.12.751153},
  url = {https://www.biorxiv.org/content/10.64898/2026.09.12.751153v1},
  note = {CC BY},
}
RIS
TY  - UNPB
TI  - Mechanistical and structural basis of Kv channel inhibition by 4 aminopyridine
AU  - B. I. Pinto-Anwandter
AU  - R. Agrawal
AU  - T. Thomas
AU  - E. Perozo
AU  - B. Roux
AU  - F. Bezanilla
PY  - 2026
DA  - 2026/09/12
PB  - bioRxiv
DO  - 10.64898/2026.09.12.751153
UR  - https://www.biorxiv.org/content/10.64898/2026.09.12.751153v1
AB  - Inhibition of Kv channels by 4-aminopyridine (4AP) improves motor function in multiple sclerosis by enhancing neuronal excitability. The mechanism of inhibition and the structural basis of 4AP binding to Kv channels remain unclear. Here, we determined the structure of the Shaker V369I-I372L-S376T (ILT) mutant bound to 4AP at 3.3 [A], demonstrating that 4AP binds to the closed state of the channel. This structure is inconsistent with an open channel block mechanism. Electrophysiology experiments show that 4AP binds even when intracellular pore access is constitutively blocked, suggesting that 4AP enters the pore through membrane-facing fenestrations. MD simulations and mutational analysis agree with the proposed fenestration pathway and suggest that 4AP binds in its neutral form. These results support a mechanism where 4AP binds to a partially activated closed state that prevents complete activation of Kv channels, explaining its pharmacological activity.
ER  -