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Chemical basis for the recognition of trimethyllysine by epigenetic reader proteins

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  • Jos J.A.G. Kamps

    (Institute for Molecules and Materials, Radboud University, Heyendaalseweg 135)

  • Jiaxin Huang

    (Center for Structural Biology, School of Medicine, Tsinghua University)

  • Jordi Poater

    (VU University, De Boelelaan 1083)

  • Chao Xu

    (Structural Genomics Consortium, University of Toronto, 101 College Street, Toronto)

  • Bas J.G.E. Pieters

    (Institute for Molecules and Materials, Radboud University, Heyendaalseweg 135)

  • Aiping Dong

    (Structural Genomics Consortium, University of Toronto, 101 College Street, Toronto)

  • Jinrong Min

    (Structural Genomics Consortium, University of Toronto, 101 College Street, Toronto)

  • Woody Sherman

    (Schrödinger, Inc., 120 West 45th Street)

  • Thijs Beuming

    (Schrödinger, Inc., 120 West 45th Street)

  • F. Matthias Bickelhaupt

    (Institute for Molecules and Materials, Radboud University, Heyendaalseweg 135
    VU University, De Boelelaan 1083)

  • Haitao Li

    (Center for Structural Biology, School of Medicine, Tsinghua University)

  • Jasmin Mecinović

    (Institute for Molecules and Materials, Radboud University, Heyendaalseweg 135)

Abstract

A large number of structurally diverse epigenetic reader proteins specifically recognize methylated lysine residues on histone proteins. Here we describe comparative thermodynamic, structural and computational studies on recognition of the positively charged natural trimethyllysine and its neutral analogues by reader proteins. This work provides experimental and theoretical evidence that reader proteins predominantly recognize trimethyllysine via a combination of favourable cation–π interactions and the release of the high-energy water molecules that occupy the aromatic cage of reader proteins on the association with the trimethyllysine side chain. These results have implications in rational drug design by specifically targeting the aromatic cage of readers of trimethyllysine.

Suggested Citation

  • Jos J.A.G. Kamps & Jiaxin Huang & Jordi Poater & Chao Xu & Bas J.G.E. Pieters & Aiping Dong & Jinrong Min & Woody Sherman & Thijs Beuming & F. Matthias Bickelhaupt & Haitao Li & Jasmin Mecinović, 2015. "Chemical basis for the recognition of trimethyllysine by epigenetic reader proteins," Nature Communications, Nature, vol. 6(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9911
    DOI: 10.1038/ncomms9911
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