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

Jacob Lauwring Andersen; Borbala Gesser; Erik Daa Funder; Christine Juul Fælled Nielsen; Helle Gotfred-Rasmussen; Mads Kirchheiner Rasmussen; Rachel Toth; Kurt Vesterager Gothelf; J. Simon C. Arthur; Lars Iversen; Poul Nissen

doi:10.1038/s41467-018-06787-w

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

Jacob Lauwring Andersen, Borbala Gesser, Erik Daa Funder, Christine Juul Fælled Nielsen, Helle Gotfred-Rasmussen, Mads Kirchheiner Rasmussen, Rachel Toth, Kurt Vesterager Gothelf, J. Simon C. Arthur, Lars Iversen, Poul Nissen

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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 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.

Original language	English
Article number	4344
Journal	Nature Communications
Volume	9
Issue	1
Number of pages	8
ISSN	2041-1723
DOIs	https://doi.org/10.1038/s41467-018-06787-w
Publication status	Published - 19 Oct 2018

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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",

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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.

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JO - Nature Communications

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ER -

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

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