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Dynamic behavior of the post‐SET loop region of NSD1: Implications for histone binding and drug development
Author(s) -
Graham Sarah E.,
Tweedy Sara E.,
Carlson Heather A.
Publication year - 2016
Publication title -
protein science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.353
H-Index - 175
eISSN - 1469-896X
pISSN - 0961-8368
DOI - 10.1002/pro.2912
Subject(s) - histone , histone h3 , histone methyltransferase , chemistry , loop (graph theory) , peptide , lysine , biophysics , stereochemistry , biochemistry , biology , amino acid , mathematics , dna , combinatorics
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.