Structural Basis for a Bimodal Allosteric Mechanism of General Anesthetic Modulation in Pentameric Ligand-Gated Ion Channels

Department of Drug Design and Pharmacology

Structural Basis for a Bimodal Allosteric Mechanism of General Anesthetic Modulation in Pentameric Ligand-Gated Ion Channels

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Structural Basis for a Bimodal Allosteric Mechanism of General Anesthetic Modulation in Pentameric Ligand-Gated Ion Channels. / Fourati, Zaineb; Howard, Rebecca J; Heusser, Stephanie A; Hu, Haidai; Ruza, Reinis R; Sauguet, Ludovic; Lindahl, Erik; Delarue, Marc.

In: Cell Reports, Vol. 23, No. 4, 24.04.2018, p. 993-1004.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Fourati, Z, Howard, RJ, Heusser, SA, Hu, H, Ruza, RR, Sauguet, L, Lindahl, E & Delarue, M 2018, 'Structural Basis for a Bimodal Allosteric Mechanism of General Anesthetic Modulation in Pentameric Ligand-Gated Ion Channels', Cell Reports, vol. 23, no. 4, pp. 993-1004. https://doi.org/10.1016/j.celrep.2018.03.108

APA

Fourati, Z., Howard, R. J., Heusser, S. A., Hu, H., Ruza, R. R., Sauguet, L., Lindahl, E., & Delarue, M. (2018). Structural Basis for a Bimodal Allosteric Mechanism of General Anesthetic Modulation in Pentameric Ligand-Gated Ion Channels. Cell Reports, 23(4), 993-1004. https://doi.org/10.1016/j.celrep.2018.03.108

Vancouver

Fourati Z, Howard RJ, Heusser SA, Hu H, Ruza RR, Sauguet L et al. Structural Basis for a Bimodal Allosteric Mechanism of General Anesthetic Modulation in Pentameric Ligand-Gated Ion Channels. Cell Reports. 2018 Apr 24;23(4):993-1004. https://doi.org/10.1016/j.celrep.2018.03.108

Author

Fourati, Zaineb ; Howard, Rebecca J ; Heusser, Stephanie A ; Hu, Haidai ; Ruza, Reinis R ; Sauguet, Ludovic ; Lindahl, Erik ; Delarue, Marc. / Structural Basis for a Bimodal Allosteric Mechanism of General Anesthetic Modulation in Pentameric Ligand-Gated Ion Channels. In: Cell Reports. 2018 ; Vol. 23, No. 4. pp. 993-1004.

Bibtex

@article{0876eafde0704199a4167f6acff94cdf,

title = "Structural Basis for a Bimodal Allosteric Mechanism of General Anesthetic Modulation in Pentameric Ligand-Gated Ion Channels",

abstract = "Ion channel modulation by general anesthetics is a vital pharmacological process with implications for receptor biophysics and drug development. Functional studies have implicated conserved sites of both potentiation and inhibition in pentameric ligand-gated ion channels, but a detailed structural mechanism for these bimodal effects is lacking. The prokaryotic model protein GLIC recapitulates anesthetic modulation of human ion channels, and it is accessible to structure determination in both apparent open and closed states. Here, we report ten X-ray structures and electrophysiological characterization of GLIC variants in the presence and absence of general anesthetics, including the surgical agent propofol. We show that general anesthetics can allosterically favor closed channels by binding in the pore or favor open channels via various subsites in the transmembrane domain. Our results support an integrated, multi-site mechanism for allosteric modulation, and they provide atomic details of both potentiation and inhibition by one of the most common general anesthetics.",

author = "Zaineb Fourati and Howard, {Rebecca J} and Heusser, {Stephanie A} and Haidai Hu and Ruza, {Reinis R} and Ludovic Sauguet and Erik Lindahl and Marc Delarue",

year = "2018",

month = apr,

day = "24",

doi = "10.1016/j.celrep.2018.03.108",

language = "English",

volume = "23",

pages = "993--1004",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "4",

}

RIS

TY - JOUR

T1 - Structural Basis for a Bimodal Allosteric Mechanism of General Anesthetic Modulation in Pentameric Ligand-Gated Ion Channels

AU - Fourati, Zaineb

AU - Howard, Rebecca J

AU - Heusser, Stephanie A

AU - Hu, Haidai

AU - Ruza, Reinis R

AU - Sauguet, Ludovic

AU - Lindahl, Erik

AU - Delarue, Marc

PY - 2018/4/24

Y1 - 2018/4/24

N2 - Ion channel modulation by general anesthetics is a vital pharmacological process with implications for receptor biophysics and drug development. Functional studies have implicated conserved sites of both potentiation and inhibition in pentameric ligand-gated ion channels, but a detailed structural mechanism for these bimodal effects is lacking. The prokaryotic model protein GLIC recapitulates anesthetic modulation of human ion channels, and it is accessible to structure determination in both apparent open and closed states. Here, we report ten X-ray structures and electrophysiological characterization of GLIC variants in the presence and absence of general anesthetics, including the surgical agent propofol. We show that general anesthetics can allosterically favor closed channels by binding in the pore or favor open channels via various subsites in the transmembrane domain. Our results support an integrated, multi-site mechanism for allosteric modulation, and they provide atomic details of both potentiation and inhibition by one of the most common general anesthetics.

AB - Ion channel modulation by general anesthetics is a vital pharmacological process with implications for receptor biophysics and drug development. Functional studies have implicated conserved sites of both potentiation and inhibition in pentameric ligand-gated ion channels, but a detailed structural mechanism for these bimodal effects is lacking. The prokaryotic model protein GLIC recapitulates anesthetic modulation of human ion channels, and it is accessible to structure determination in both apparent open and closed states. Here, we report ten X-ray structures and electrophysiological characterization of GLIC variants in the presence and absence of general anesthetics, including the surgical agent propofol. We show that general anesthetics can allosterically favor closed channels by binding in the pore or favor open channels via various subsites in the transmembrane domain. Our results support an integrated, multi-site mechanism for allosteric modulation, and they provide atomic details of both potentiation and inhibition by one of the most common general anesthetics.

U2 - 10.1016/j.celrep.2018.03.108

DO - 10.1016/j.celrep.2018.03.108

M3 - Journal article

C2 - 29694907

VL - 23

SP - 993

EP - 1004

JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

IS - 4

ER -

ID: 203550684