Department of Biochemistry, Albert Einstein College of Medicine , 1300 Morris Park Avenue, Bronx, New York 10461, United States.
Biological Sciences, Platform Technology and Science, GlaxoSmithKline , Collegeville, Pennsylvania 19426, United States.
J Am Chem Soc. 2016 Jun 1;138(21):6699-702. doi: 10.1021/jacs.6b01612. Epub 2016 May 23.
Nuclear receptor-binding SET domain protein 2 (NSD2) is a histone H3 lysine 36 (H3K36)-specific methyltransferase enzyme that is overexpressed in a number of cancers, including multiple myeloma. NSD2 binds to S-adenosyl-l-methionine (SAM) and nucleosome substrates to catalyze the transfer of a methyl group from SAM to the ε-amino group of histone H3K36. Equilibrium binding isotope effects and density functional theory calculations indicate that the SAM methyl group is sterically constrained in complex with NSD2, and that this steric constraint is released upon nucleosome binding. Together, these results show that nucleosome binding to NSD2 induces a significant change in the chemical environment of enzyme-bound SAM.
核受体结合 SET 域蛋白 2（NSD2）是一种组蛋白 H3 赖氨酸 36（H3K36）特异性甲基转移酶，在包括多发性骨髓瘤在内的多种癌症中过表达。NSD2 与 S-腺苷甲硫氨酸（SAM）和核小体底物结合，催化甲基从 SAM 转移到组蛋白 H3K36 的 ε-氨基。平衡结合同位素效应和密度泛函理论计算表明，SAM 甲基在与 NSD2 形成复合物时受到空间位阻限制，而这种空间位阻在与核小体结合时被释放。总之，这些结果表明，核小体与 NSD2 的结合诱导了酶结合的 SAM 化学环境的显著变化。
