title: Dynamic behavior of the post-SET loop region of NSD1: Implications for histone binding and drug development.
abstract: NSD1 is a SET-domain histone methyltransferase that methylates lysine 36 of histone 3. In the crystal structure of NSD1, the post-SET loop is in an autoinhibitory position that blocks binding of the histone peptide as well as the entrance to the lysine-binding channel. The conformational dynamics preceding histone binding and the mechanism by which the post-SET loop moves to accommodate the target lysine is currently unknown, although potential models have been proposed. Using molecular dynamics simulations, we have identified potential conformations of the post-SET loop differing from those of previous studies, as well as proposed a model of peptide-bound NSD1. Our simulations illustrate the dynamic behavior of the post-SET loop and the presence of a few distinct conformations. In every case, the post-SET loop remains in an autoinhibitory position blocking the peptide-binding cleft, suggesting that another interaction is required to optimally position NSD1 in an active conformation. This finding provides initial evidence for a mechanism by which NSD1 preferentially binds nucleosomal substrates.
authors.affiliation: Department of Biophysics, University of Michigan, Ann Arbor, Michigan, 48109-1055.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Graham
authors.affiliation: Department of Chemistry, Harvey Mudd College, Claremont, California, 91711-5901.
authors.forename: Sara E
authors.initials: SE
authors.lastname: Tweedy
authors.affiliation: Department of Biophysics, University of Michigan, Ann Arbor, Michigan, 48109-1055.|Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, 48109-1065.
authors.forename: Heather A
authors.initials: HA
authors.lastname: Carlson
mesh_terms: D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D015195:Drug Design; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry* / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009687:Nuclear Proteins / Q000737:chemistry* / Q000378:metabolism*; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship
chemical_list: D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C113272:NSD1 protein, human; D008239:Lysine
keywords: NSD family; cancer; histone methyltransferase; molecular dynamics; structure-based drug design