title: Chemical basis for the recognition of trimethyllysine by epigenetic reader proteins.
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.
authors.affiliation: Institute for Molecules and Materials, Radboud University, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands.
authors.forename: Jos J A G
authors.initials: JJ
authors.lastname: Kamps
authors.affiliation: Department of Basic Medical Sciences, Center for Structural Biology, School of Medicine, Tsinghua University, Beijing 100084, China.
authors.forename: Jiaxin
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Theoretical Chemistry and Amsterdam Center for Multiscale Modeling, VU University, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
authors.forename: Jordi
authors.initials: J
authors.lastname: Poater
authors.affiliation: Structural Genomics Consortium, University of Toronto, 101 College Street, Toronto, Ontario, Canada M5G 1L7.
authors.forename: Chao
authors.identifier: http://orcid.org/0000-0003-0444-7080
authors.initials: C
authors.lastname: Xu
authors.affiliation: Institute for Molecules and Materials, Radboud University, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands.
authors.forename: Bas J G E
authors.initials: BJ
authors.lastname: Pieters
authors.affiliation: Structural Genomics Consortium, University of Toronto, 101 College Street, Toronto, Ontario, Canada M5G 1L7.
authors.forename: Aiping
authors.initials: A
authors.lastname: Dong
authors.affiliation: Structural Genomics Consortium, University of Toronto, 101 College Street, Toronto, Ontario, Canada M5G 1L7.
authors.forename: Jinrong
authors.initials: J
authors.lastname: Min
authors.affiliation: Schrödinger, Inc., 120 West 45th Street, New York, New York 10036 USA.
authors.forename: Woody
authors.initials: W
authors.lastname: Sherman
authors.affiliation: Schrödinger, Inc., 120 West 45th Street, New York, New York 10036 USA.
authors.forename: Thijs
authors.initials: T
authors.lastname: Beuming
authors.affiliation: Institute for Molecules and Materials, Radboud University, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands.|Department of Theoretical Chemistry and Amsterdam Center for Multiscale Modeling, VU University, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
authors.forename: F
authors.identifier: http://orcid.org/0000-0003-4655-7747
authors.initials: F
authors.lastname: Matthias Bickelhaupt
authors.affiliation: Department of Basic Medical Sciences, Center for Structural Biology, School of Medicine, Tsinghua University, Beijing 100084, China.
authors.forename: Haitao
authors.initials: H
authors.lastname: Li
authors.affiliation: Institute for Molecules and Materials, Radboud University, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Mecinović
mesh_terms: D000123:Acetyltransferases / Q000737:chemistry*; D024322:Amino Acids, Aromatic / Q000737:chemistry; D034961:Antigens, Nuclear / Q000737:chemistry*; D002151:Calorimetry; D018360:Crystallography, X-Ray; D044127:Epigenesis, Genetic; D042421:Histone Code; D006657:Histones / Q000378:metabolism*; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000737:chemistry*; D008239:Lysine / Q000031:analogs & derivatives* / Q000737:chemistry; D008745:Methylation; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009419:Nerve Tissue Proteins / Q000737:chemistry*; D000644:Quaternary Ammonium Compounds; D056485:Retinoblastoma-Binding Protein 2 / Q000737:chemistry*; D035381:TATA-Binding Protein Associated Factors; D035362:Transcription Factor TFIID / Q000737:chemistry*; D014157:Transcription Factors / Q000737:chemistry*; D000092468:Bromodomain Containing Proteins
chemical_list: D000123:Acetyltransferases; D024322:Amino Acids, Aromatic; D034961:Antigens, Nuclear; D006657:Histones; D056484:Jumonji Domain-Containing Histone Demethylases; D008239:Lysine; D009419:Nerve Tissue Proteins; D000644:Quaternary Ammonium Compounds; D056485:Retinoblastoma-Binding Protein 2; D035381:TATA-Binding Protein Associated Factors; D035362:Transcription Factor TFIID; D014157:Transcription Factors; C432689:TAF3 protein, human; C406238:fetal Alzheimer antigen; D000092468:Bromodomain Containing Proteins; C003712:trimethyllysine; C070050:KDM5A protein, human; C494424:KDM4A protein, human; C561317:Sgf29 protein, human