Chemical substitutions in the selectivity filter of potassium channels do not rule out constricted-like conformations for C-type inactivation

Jing Li, Jared Ostmeyer, Eliot Boulanger, Huan Rui, Eduardo Perozo, Benoît Roux

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

In many K+ channels, prolonged activating stimuli lead to a time-dependent reduction in ion conduction, a phenomenon known as C-type inactivation. X-ray structures of the KcsA channel suggest that this inactivated state corresponds to a “constricted” conformation of the selectivity filter. However, the functional significance of the constricted conformation has become a matter of debate. Functional and structural studies based on chemically modified semisynthetic KcsA channels along the selectivity filter led to the conclusion that the constricted conformation does not correspond to the C-type inactivated state. The main results supporting this view include the observation that C-type inactivation is not suppressed by a substitution of D-alanine at Gly77, even though this modification is believed to lock the selectivity filter into its conductive conformation, whereas it is suppressed following amide-to-ester backbone substitutions at Gly77 and Tyr78, even though these structure-conserving modifications are not believed to prevent the selectivity filter from adopting the constricted conformation. However, several untested assumptions about the structural and functional impact of these chemical modifications underlie these arguments. To make progress, molecular dynamics simulations based on atomic models of the KcsA channel were performed. The computational results support the notion that the constricted conformation of the selectivity filter corresponds to the functional C-type inactivated state of the KcsA. Importantly, MD simulations reveal that the semisynthetic KcsAD-ala77 channel can adopt an asymmetrical constricted-like nonconductive conformation and that the amide-to-ester backbone substitutions at Gly77 and Tyr78 perturb the hydrogen bonding involving the buried water molecules stabilizing the constricted conformation.

Original languageEnglish (US)
Pages (from-to)11145-11150
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number42
DOIs
StatePublished - Oct 17 2017
Externally publishedYes

Fingerprint

Potassium Channels
Amides
Esters
Molecular Dynamics Simulation
Hydrogen Bonding
Alanine
X-Rays
Ions
Water

Keywords

  • Free energy
  • Inactivation
  • Ion channel
  • Molecular dynamics
  • Water

ASJC Scopus subject areas

  • General

Cite this

Chemical substitutions in the selectivity filter of potassium channels do not rule out constricted-like conformations for C-type inactivation. / Li, Jing; Ostmeyer, Jared; Boulanger, Eliot; Rui, Huan; Perozo, Eduardo; Roux, Benoît.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 42, 17.10.2017, p. 11145-11150.

Research output: Contribution to journalArticle

@article{33f224dd6fd546bcb5b206c9c7262c0b,
title = "Chemical substitutions in the selectivity filter of potassium channels do not rule out constricted-like conformations for C-type inactivation",
abstract = "In many K+ channels, prolonged activating stimuli lead to a time-dependent reduction in ion conduction, a phenomenon known as C-type inactivation. X-ray structures of the KcsA channel suggest that this inactivated state corresponds to a “constricted” conformation of the selectivity filter. However, the functional significance of the constricted conformation has become a matter of debate. Functional and structural studies based on chemically modified semisynthetic KcsA channels along the selectivity filter led to the conclusion that the constricted conformation does not correspond to the C-type inactivated state. The main results supporting this view include the observation that C-type inactivation is not suppressed by a substitution of D-alanine at Gly77, even though this modification is believed to lock the selectivity filter into its conductive conformation, whereas it is suppressed following amide-to-ester backbone substitutions at Gly77 and Tyr78, even though these structure-conserving modifications are not believed to prevent the selectivity filter from adopting the constricted conformation. However, several untested assumptions about the structural and functional impact of these chemical modifications underlie these arguments. To make progress, molecular dynamics simulations based on atomic models of the KcsA channel were performed. The computational results support the notion that the constricted conformation of the selectivity filter corresponds to the functional C-type inactivated state of the KcsA. Importantly, MD simulations reveal that the semisynthetic KcsAD-ala77 channel can adopt an asymmetrical constricted-like nonconductive conformation and that the amide-to-ester backbone substitutions at Gly77 and Tyr78 perturb the hydrogen bonding involving the buried water molecules stabilizing the constricted conformation.",
keywords = "Free energy, Inactivation, Ion channel, Molecular dynamics, Water",
author = "Jing Li and Jared Ostmeyer and Eliot Boulanger and Huan Rui and Eduardo Perozo and Beno{\^i}t Roux",
year = "2017",
month = "10",
day = "17",
doi = "10.1073/pnas.1706983114",
language = "English (US)",
volume = "114",
pages = "11145--11150",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "42",

}

TY - JOUR

T1 - Chemical substitutions in the selectivity filter of potassium channels do not rule out constricted-like conformations for C-type inactivation

AU - Li, Jing

AU - Ostmeyer, Jared

AU - Boulanger, Eliot

AU - Rui, Huan

AU - Perozo, Eduardo

AU - Roux, Benoît

PY - 2017/10/17

Y1 - 2017/10/17

N2 - In many K+ channels, prolonged activating stimuli lead to a time-dependent reduction in ion conduction, a phenomenon known as C-type inactivation. X-ray structures of the KcsA channel suggest that this inactivated state corresponds to a “constricted” conformation of the selectivity filter. However, the functional significance of the constricted conformation has become a matter of debate. Functional and structural studies based on chemically modified semisynthetic KcsA channels along the selectivity filter led to the conclusion that the constricted conformation does not correspond to the C-type inactivated state. The main results supporting this view include the observation that C-type inactivation is not suppressed by a substitution of D-alanine at Gly77, even though this modification is believed to lock the selectivity filter into its conductive conformation, whereas it is suppressed following amide-to-ester backbone substitutions at Gly77 and Tyr78, even though these structure-conserving modifications are not believed to prevent the selectivity filter from adopting the constricted conformation. However, several untested assumptions about the structural and functional impact of these chemical modifications underlie these arguments. To make progress, molecular dynamics simulations based on atomic models of the KcsA channel were performed. The computational results support the notion that the constricted conformation of the selectivity filter corresponds to the functional C-type inactivated state of the KcsA. Importantly, MD simulations reveal that the semisynthetic KcsAD-ala77 channel can adopt an asymmetrical constricted-like nonconductive conformation and that the amide-to-ester backbone substitutions at Gly77 and Tyr78 perturb the hydrogen bonding involving the buried water molecules stabilizing the constricted conformation.

AB - In many K+ channels, prolonged activating stimuli lead to a time-dependent reduction in ion conduction, a phenomenon known as C-type inactivation. X-ray structures of the KcsA channel suggest that this inactivated state corresponds to a “constricted” conformation of the selectivity filter. However, the functional significance of the constricted conformation has become a matter of debate. Functional and structural studies based on chemically modified semisynthetic KcsA channels along the selectivity filter led to the conclusion that the constricted conformation does not correspond to the C-type inactivated state. The main results supporting this view include the observation that C-type inactivation is not suppressed by a substitution of D-alanine at Gly77, even though this modification is believed to lock the selectivity filter into its conductive conformation, whereas it is suppressed following amide-to-ester backbone substitutions at Gly77 and Tyr78, even though these structure-conserving modifications are not believed to prevent the selectivity filter from adopting the constricted conformation. However, several untested assumptions about the structural and functional impact of these chemical modifications underlie these arguments. To make progress, molecular dynamics simulations based on atomic models of the KcsA channel were performed. The computational results support the notion that the constricted conformation of the selectivity filter corresponds to the functional C-type inactivated state of the KcsA. Importantly, MD simulations reveal that the semisynthetic KcsAD-ala77 channel can adopt an asymmetrical constricted-like nonconductive conformation and that the amide-to-ester backbone substitutions at Gly77 and Tyr78 perturb the hydrogen bonding involving the buried water molecules stabilizing the constricted conformation.

KW - Free energy

KW - Inactivation

KW - Ion channel

KW - Molecular dynamics

KW - Water

UR - http://www.scopus.com/inward/record.url?scp=85031319238&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85031319238&partnerID=8YFLogxK

U2 - 10.1073/pnas.1706983114

DO - 10.1073/pnas.1706983114

M3 - Article

C2 - 28973956

AN - SCOPUS:85031319238

VL - 114

SP - 11145

EP - 11150

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 42

ER -