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Poul Nissen

Dimethyl fumarate is an allosteric covalent inhibitor of the p90 ribosomal S6 kinases

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Dimethyl fumarate is an allosteric covalent inhibitor of the p90 ribosomal S6 kinases. / Andersen, Jacob Lauwring; Gesser, Borbala; Funder, Erik Daa; Nielsen, Christine Juul Fælled; Gotfred-Rasmussen, Helle; Rasmussen, Mads Kirchheiner; Toth, Rachel; Gothelf, Kurt Vesterager; Arthur, J. Simon C.; Iversen, Lars; Nissen, Poul.

In: Nature Communications, Vol. 9, No. 1, 4344, 19.10.2018.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Harvard

Andersen, JL, Gesser, B, Funder, ED, Nielsen, CJF, Gotfred-Rasmussen, H, Rasmussen, MK, Toth, R, Gothelf, KV, Arthur, JSC, Iversen, L & Nissen, P 2018, 'Dimethyl fumarate is an allosteric covalent inhibitor of the p90 ribosomal S6 kinases', Nature Communications, vol. 9, no. 1, 4344. https://doi.org/10.1038/s41467-018-06787-w

APA

Andersen, J. L., Gesser, B., Funder, E. D., Nielsen, C. J. F., Gotfred-Rasmussen, H., Rasmussen, M. K., Toth, R., Gothelf, K. V., Arthur, J. S. C., Iversen, L., & Nissen, P. (2018). Dimethyl fumarate is an allosteric covalent inhibitor of the p90 ribosomal S6 kinases. Nature Communications, 9(1), [4344]. https://doi.org/10.1038/s41467-018-06787-w

CBE

Andersen JL, Gesser B, Funder ED, Nielsen CJF, Gotfred-Rasmussen H, Rasmussen MK, Toth R, Gothelf KV, Arthur JSC, Iversen L, Nissen P. 2018. Dimethyl fumarate is an allosteric covalent inhibitor of the p90 ribosomal S6 kinases. Nature Communications. 9(1):Article 4344. https://doi.org/10.1038/s41467-018-06787-w

MLA

Vancouver

Andersen JL, Gesser B, Funder ED, Nielsen CJF, Gotfred-Rasmussen H, Rasmussen MK et al. Dimethyl fumarate is an allosteric covalent inhibitor of the p90 ribosomal S6 kinases. Nature Communications. 2018 Oct 19;9(1). 4344. https://doi.org/10.1038/s41467-018-06787-w

Author

Andersen, Jacob Lauwring ; Gesser, Borbala ; Funder, Erik Daa ; Nielsen, Christine Juul Fælled ; Gotfred-Rasmussen, Helle ; Rasmussen, Mads Kirchheiner ; Toth, Rachel ; Gothelf, Kurt Vesterager ; Arthur, J. Simon C. ; Iversen, Lars ; Nissen, Poul. / Dimethyl fumarate is an allosteric covalent inhibitor of the p90 ribosomal S6 kinases. In: Nature Communications. 2018 ; Vol. 9, No. 1.

Bibtex

@article{ff27ac5394094678aaeea1e66d966606,
title = "Dimethyl fumarate is an allosteric covalent inhibitor of the p90 ribosomal S6 kinases",
abstract = "Dimethyl fumarate (DMF) has been applied for decades in the treatment of psoriasis and now also multiple sclerosis. However, the mechanism of action has remained obscure and involves high dose over long time of this small, reactive compound implicating many potential targets. Based on a 1.9 {\AA} resolution crystal structure of the C-terminal kinase domain of the mouse p90 Ribosomal S6 Kinase 2 (RSK2) inhibited by DMF we describe a central binding site in RSKs and the closely related Mitogen and Stress-activated Kinases (MSKs). DMF reacts covalently as a Michael acceptor to a conserved cysteine residue in the αF-helix of RSK/MSKs. Binding of DMF prevents the activation loop of the kinase from engaging substrate, and stabilizes an auto-inhibitory αL-helix, thus pointing to an effective, allosteric mechanism of kinase inhibition. The biochemical and cell biological characteristics of DMF inhibition of RSK/MSKs are consistent with the clinical protocols of DMF treatment.",
author = "Andersen, {Jacob Lauwring} and Borbala Gesser and Funder, {Erik Daa} and Nielsen, {Christine Juul F{\ae}lled} and Helle Gotfred-Rasmussen and Rasmussen, {Mads Kirchheiner} and Rachel Toth and Gothelf, {Kurt Vesterager} and Arthur, {J. Simon C.} and Lars Iversen and Poul Nissen",
year = "2018",
month = oct,
day = "19",
doi = "10.1038/s41467-018-06787-w",
language = "English",
volume = "9",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",

}

RIS

TY - JOUR

T1 - Dimethyl fumarate is an allosteric covalent inhibitor of the p90 ribosomal S6 kinases

AU - Andersen, Jacob Lauwring

AU - Gesser, Borbala

AU - Funder, Erik Daa

AU - Nielsen, Christine Juul Fælled

AU - Gotfred-Rasmussen, Helle

AU - Rasmussen, Mads Kirchheiner

AU - Toth, Rachel

AU - Gothelf, Kurt Vesterager

AU - Arthur, J. Simon C.

AU - Iversen, Lars

AU - Nissen, Poul

PY - 2018/10/19

Y1 - 2018/10/19

N2 - Dimethyl fumarate (DMF) has been applied for decades in the treatment of psoriasis and now also multiple sclerosis. However, the mechanism of action has remained obscure and involves high dose over long time of this small, reactive compound implicating many potential targets. Based on a 1.9 Å resolution crystal structure of the C-terminal kinase domain of the mouse p90 Ribosomal S6 Kinase 2 (RSK2) inhibited by DMF we describe a central binding site in RSKs and the closely related Mitogen and Stress-activated Kinases (MSKs). DMF reacts covalently as a Michael acceptor to a conserved cysteine residue in the αF-helix of RSK/MSKs. Binding of DMF prevents the activation loop of the kinase from engaging substrate, and stabilizes an auto-inhibitory αL-helix, thus pointing to an effective, allosteric mechanism of kinase inhibition. The biochemical and cell biological characteristics of DMF inhibition of RSK/MSKs are consistent with the clinical protocols of DMF treatment.

AB - Dimethyl fumarate (DMF) has been applied for decades in the treatment of psoriasis and now also multiple sclerosis. However, the mechanism of action has remained obscure and involves high dose over long time of this small, reactive compound implicating many potential targets. Based on a 1.9 Å resolution crystal structure of the C-terminal kinase domain of the mouse p90 Ribosomal S6 Kinase 2 (RSK2) inhibited by DMF we describe a central binding site in RSKs and the closely related Mitogen and Stress-activated Kinases (MSKs). DMF reacts covalently as a Michael acceptor to a conserved cysteine residue in the αF-helix of RSK/MSKs. Binding of DMF prevents the activation loop of the kinase from engaging substrate, and stabilizes an auto-inhibitory αL-helix, thus pointing to an effective, allosteric mechanism of kinase inhibition. The biochemical and cell biological characteristics of DMF inhibition of RSK/MSKs are consistent with the clinical protocols of DMF treatment.

UR - http://www.scopus.com/inward/record.url?scp=85055075647&partnerID=8YFLogxK

U2 - 10.1038/s41467-018-06787-w

DO - 10.1038/s41467-018-06787-w

M3 - Journal article

C2 - 30341347

AN - SCOPUS:85055075647

VL - 9

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 4344

ER -