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Structural Dynamics of the NSD Family Histone Methyltransferases
Author(s) -
Teichert Kristian,
Iacob Roxana,
St. Pierre Roodolph,
Ishoey Mette,
Chen Sixun,
Paulk Joshiawa,
Engen John,
Bradner James
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.717.13
Subject(s) - methyltransferase , methylation , histone , chemistry , histone methyltransferase , bromodomain , computational biology , demethylase , dna , cancer research , biochemistry , biology
The nuclear SET domain containing protein (NSD) family of histone methyltransferases is an oncogenic family of proteins, whose overexpression is directly involved in cancers, such as acute lymphoblastic leukemia (ALL) and breast cancer. The NSD family consists of three proteins NSD1, NSD2 and NSD3. These proteins are directly responsible for the methylation of multiple lysine residues of histones, a post‐translational modification implicated in transcription‐activating cell survival mechanisms and DNA damage responses. NSD2 in particular is a high‐profile target for inhibition, because it is overexpressed in 20% of multiple myeloma cases. Both NSD2 and NSD3 have evaded crystallization efforts, and only the SET domain of NSD1 has been crystallized. In the absence of a crystal structure for NSD2 and NSD3, we employed homology modeling of the SET domains of NSD2 and NSD3 and hydrogen‐deuterium exchange mass spectrometry (HDX MS) in order to obtain information about the conformation and dynamics of the SET domain in NSD family proteins. HDX MS was also used to monitor and localize binding of drug candidates directed against these proteins. Our results can aid the development of specific inhibitors for members of the NSD family. Support: R21 CA179159‐01A1, Multiple Myeloma Research Foundation Collaborative PPG