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Biophys J. 2019 Jul 23;117(2):377-387. doi: 10.1016/j.bpj.2019.06.008. Epub 2019 Jun 14.

A Structural Model of the Inactivation Gate of Voltage-Activated Potassium Channels.

Author information

1
Multidisciplinary Scientific Nucleus, Center for Bioinformatics and Molecular Simulation; Millennium Nucleus of Ion Channels-associated Diseases (MiNICAD), Universidad de Talca, Talca, Chile; Institute of Computational Comparative Medicine, Nanotechnology Innovation Center of Kansas State, Department of Anatomy and Physiology, Kansas State University, Manhattan, Kansas.
2
Molecular Neurophysiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.
3
Institute of Computational Comparative Medicine, Nanotechnology Innovation Center of Kansas State, Department of Anatomy and Physiology, Kansas State University, Manhattan, Kansas. Electronic address: jeffcomer@ksu.edu.
4
Molecular Neurophysiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland. Electronic address: holmgren@ninds.nih.gov.

Abstract

After opening, the Shaker voltage-gated potassium (KV) channel rapidly inactivates when one of its four N-termini enters and occludes the channel pore. Although it is known that the tip of the N-terminus reaches deep into the central cavity, the conformation adopted by this domain during inactivation and the nature of its interactions with the rest of the channel remain unclear. Here, we use molecular dynamics simulations coupled with electrophysiology experiments to reveal the atomic-scale mechanisms of inactivation. We find that the first six amino acids of the N-terminus spontaneously enter the central cavity in an extended conformation, establishing hydrophobic contacts with residues lining the pore. A second portion of the N-terminus, consisting of a long 24 amino acid α-helix, forms numerous polar contacts with residues in the intracellular entryway of the T1 domain. Double mutant cycle analysis revealed a strong relationship between predicted interatomic distances and empirically observed thermodynamic coupling, establishing a plausible model of the transition of KV channels to the inactivated state.

PMID:
31278002
DOI:
10.1016/j.bpj.2019.06.008

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