Dynamic behavior of the post‐SET loop region of NSD1: Implications for histone binding and drug development |
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Authors: | Sarah E. Graham Sara E. Tweedy Heather A. Carlson |
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Affiliation: | 1. Department of Biophysics, University of Michigan, Ann Arbor, Michigan;2. Department of Chemistry, Harvey Mudd College, Claremont, California;3. Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan |
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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. |
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Keywords: | histone methyltransferase NSD family cancer structure‐based drug design molecular dynamics |
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