Mechanism of biomolecular recognition of trimethyllysine by the fluorinated aromatic cage of KDM5A PHD3 finger

Bas J.G.E. Pieters; Maud H.M. Wuts; Jordi Poater; Kiran Kumar; Paul B. White; Jos J.A.G. Kamps; Woody Sherman; Ger J.M. Pruijn; Robert S. Paton; Thijs Beuming; F. Matthias Bickelhaupt; Jasmin Mecinović

doi:10.1038/s42004-020-0313-2

Mechanism of biomolecular recognition of trimethyllysine by the fluorinated aromatic cage of KDM5A PHD3 finger

Bas J.G.E. Pieters, Maud H.M. Wuts, Jordi Poater, Kiran Kumar, Paul B. White, Jos J.A.G. Kamps, Woody Sherman, Ger J.M. Pruijn, Robert S. Paton, Thijs Beuming, F. Matthias Bickelhaupt, Jasmin Mecinović^*

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

The understanding of biomolecular recognition of posttranslationally modified histone proteins is centrally important to the histone code hypothesis. Despite extensive binding and structural studies on the readout of histones, the molecular language by which posttranslational modifications on histone proteins are read remains poorly understood. Here we report physical-organic chemistry studies on the recognition of the positively charged trimethyllysine by the electron-rich aromatic cage containing PHD3 finger of KDM5A. The aromatic character of two tryptophan residues that solely constitute the aromatic cage of KDM5A was fine-tuned by the incorporation of fluorine substituents. Our thermodynamic analyses reveal that the wild-type and fluorinated KDM5A PHD3 fingers associate equally well with trimethyllysine. This work demonstrates that the biomolecular recognition of trimethyllysine by fluorinated aromatic cages is associated with weaker cation–π interactions that are compensated by the energetically more favourable trimethyllysine-mediated release of high-energy water molecules that occupy the aromatic cage.

Original language	English
Article number	69
Pages (from-to)	1-12
Number of pages	12
Journal	Communications Chemistry
Volume	3
Issue number	1
Early online date	1 Jun 2020
DOIs	https://doi.org/10.1038/s42004-020-0313-2
Publication status	Published - 1 Dec 2020

Funding

We thank the European Research Council (ERC Starting Grant, ChemEpigen-715691, J.M.), the Netherlands Research School for Chemical Biology (NRSCB, J.M.), the Netherlands Organization for Scientific Research (NWO-ALW, NWO-CW, and NWO-EW, F.M.B.), the Generalitat de Catalunya (2017SGR348, J.P.) and the Spanish MINECO (CTQ2016-77558-R and MDM-2017-0767, J.P.) for financial support. K.K. is supported by a World Bank Education Grant. We thank Professor Nediljko Budisa for providing the auxotrophic strain and Professor Jan van Hest for helpful discussions at the early stage of the project.

Funders	Funder number
NWO-ALW
NWO-CW
NWO-EW
Netherlands Organization for Scientific Research
Netherlands Research School for Chemical Biology
World Bank Group
Horizon 2020 Framework Programme	715691
European Research Council
Generalitat de Catalunya	2017SGR348
Ministerio de Economía y Competitividad	CTQ2016-77558-R, MDM-2017-0767

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Pieters, B. J. G. E., Wuts, M. H. M., Poater, J., Kumar, K., White, P. B., Kamps, J. J. A. G., Sherman, W., Pruijn, G. J. M., Paton, R. S., Beuming, T., Bickelhaupt, F. M., & Mecinović, J. (2020). Mechanism of biomolecular recognition of trimethyllysine by the fluorinated aromatic cage of KDM5A PHD3 finger. Communications Chemistry, 3(1), 1-12. Article 69. https://doi.org/10.1038/s42004-020-0313-2

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abstract = "The understanding of biomolecular recognition of posttranslationally modified histone proteins is centrally important to the histone code hypothesis. Despite extensive binding and structural studies on the readout of histones, the molecular language by which posttranslational modifications on histone proteins are read remains poorly understood. Here we report physical-organic chemistry studies on the recognition of the positively charged trimethyllysine by the electron-rich aromatic cage containing PHD3 finger of KDM5A. The aromatic character of two tryptophan residues that solely constitute the aromatic cage of KDM5A was fine-tuned by the incorporation of fluorine substituents. Our thermodynamic analyses reveal that the wild-type and fluorinated KDM5A PHD3 fingers associate equally well with trimethyllysine. This work demonstrates that the biomolecular recognition of trimethyllysine by fluorinated aromatic cages is associated with weaker cation–π interactions that are compensated by the energetically more favourable trimethyllysine-mediated release of high-energy water molecules that occupy the aromatic cage.",

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AU - Kumar, Kiran

AU - White, Paul B.

AU - Kamps, Jos J.A.G.

AU - Sherman, Woody

AU - Pruijn, Ger J.M.

AU - Paton, Robert S.

AU - Beuming, Thijs

AU - Bickelhaupt, F. Matthias

AU - Mecinović, Jasmin

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N2 - The understanding of biomolecular recognition of posttranslationally modified histone proteins is centrally important to the histone code hypothesis. Despite extensive binding and structural studies on the readout of histones, the molecular language by which posttranslational modifications on histone proteins are read remains poorly understood. Here we report physical-organic chemistry studies on the recognition of the positively charged trimethyllysine by the electron-rich aromatic cage containing PHD3 finger of KDM5A. The aromatic character of two tryptophan residues that solely constitute the aromatic cage of KDM5A was fine-tuned by the incorporation of fluorine substituents. Our thermodynamic analyses reveal that the wild-type and fluorinated KDM5A PHD3 fingers associate equally well with trimethyllysine. This work demonstrates that the biomolecular recognition of trimethyllysine by fluorinated aromatic cages is associated with weaker cation–π interactions that are compensated by the energetically more favourable trimethyllysine-mediated release of high-energy water molecules that occupy the aromatic cage.

AB - The understanding of biomolecular recognition of posttranslationally modified histone proteins is centrally important to the histone code hypothesis. Despite extensive binding and structural studies on the readout of histones, the molecular language by which posttranslational modifications on histone proteins are read remains poorly understood. Here we report physical-organic chemistry studies on the recognition of the positively charged trimethyllysine by the electron-rich aromatic cage containing PHD3 finger of KDM5A. The aromatic character of two tryptophan residues that solely constitute the aromatic cage of KDM5A was fine-tuned by the incorporation of fluorine substituents. Our thermodynamic analyses reveal that the wild-type and fluorinated KDM5A PHD3 fingers associate equally well with trimethyllysine. This work demonstrates that the biomolecular recognition of trimethyllysine by fluorinated aromatic cages is associated with weaker cation–π interactions that are compensated by the energetically more favourable trimethyllysine-mediated release of high-energy water molecules that occupy the aromatic cage.

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Mechanism of biomolecular recognition of trimethyllysine by the fluorinated aromatic cage of KDM5A PHD3 finger

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