2. Academic Validation
  3. Chemical basis for the recognition of trimethyllysine by epigenetic reader proteins

Chemical basis for the recognition of trimethyllysine by epigenetic reader proteins

  • Nat Commun. 2015 Nov 18;6:8911. doi: 10.1038/ncomms9911.
Jos J A G Kamps 1,  Jiaxin Huang 2,  Jordi Poater 3,  Chao Xu 4,  Bas J G E Pieters 1,  Aiping Dong 4,  Jinrong Min 4,  Woody Sherman 5,  Thijs Beuming 5,  F Matthias Bickelhaupt 1 3,  Haitao Li 2,  Jasmin Mecinović 1
Affiliations

Affiliations

  • 1 Institute for Molecules and Materials, Radboud University, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands.
  • 2 Department of Basic Medical Sciences, Center for Structural Biology, School of Medicine, Tsinghua University, Beijing 100084, China.
  • 3 Department of Theoretical Chemistry and Amsterdam Center for Multiscale Modeling, VU University, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
  • 4 Structural Genomics Consortium, University of Toronto, 101 College Street, Toronto, Ontario, Canada M5G 1L7.
  • 5 Schrödinger, Inc., 120 West 45th Street, New York, New York 10036 USA.
PMID: 26578293 DOI: 10.1038/ncomms9911
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.

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