The scorpion toxin BeKm-1 blocks hERG cardiac potassium channels using an indispensable arginine residue.
FEBS Lett
; 598(8): 889-901, 2024 Apr.
Article
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| MEDLINE
| ID: mdl-38563123
ABSTRACT
BeKm-1 is a peptide toxin from scorpion venom that blocks the pore of the potassium channel hERG (Kv11.1) in the human heart. Although individual protein structures have been resolved, the structure of the complex between hERG and BeKm-1 is unknown. Here, we used molecular dynamics and ensemble docking, guided by previous double-mutant cycle analysis data, to obtain an in silico model of the hERG-BeKm-1 complex. Adding to the previous mutagenesis study of BeKm-1, our model uncovers the key role of residue Arg20, which forms three interactions (a salt bridge and hydrogen bonds) with the channel vestibule simultaneously. Replacement of this residue even by lysine weakens the interactions significantly. In accordance, the recombinantly produced BeKm-1R20K mutant exhibited dramatically decreased activity on hERG. Our model may be useful for future drug design attempts.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Arginina
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Venenos de Escorpión
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Simulación de Dinámica Molecular
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Canal de Potasio ERG1
Límite:
Animals
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Humans
Idioma:
En
Revista:
FEBS Lett
Año:
2024
Tipo del documento:
Article
País de afiliación:
Rusia