Sinefungin Derivatives as Inhibitors and Structure Probes of Protein Lysine Methyltransferase SETD2

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• 作者：Weihong Zheng ; Glorymar Ib谩帽ez ; Hong Wu ; Gil Blum ; Hong Zeng ; Aiping Dong ; Fengling Li ; Taraneh Hajian ; Abdellah Allali-Hassani ; Maria F. Amaya ; Alena Siarheyeva ; Wenyu Yu ; Peter J. Brown ; Matthieu Schapira ; Masoud Vedadi ; Jinrong Min ; Minkui Luo
• 刊名：The Journal of the American Chemical Society
• 出版年：2012
• 出版时间：October 31, 2012
• 年：2012
• 卷：134
• 期：43
• 页码：18004-18014
• 全文大小：709K
• 年卷期：v.134,no.43(October 31, 2012)
• ISSN：1520-5126

文摘

Epigenetic regulation is involved in numerous physiological and pathogenic processes. Among the key regulators that orchestrate epigenetic signaling are over 50 human protein lysine methyltransferases (PKMTs). Interrogation of the functions of individual PKMTs can be facilitated by target-specific PKMT inhibitors. Given the emerging need for such small molecules, we envisioned an approach to identify target-specific methyltransferase inhibitors by screening privileged small-molecule scaffolds against diverse methyltransferases. In this work, we demonstrated the feasibility of such an approach by identifying the inhibitors of SETD2. N-propyl sinefungin (Pr-SNF) was shown to interact preferentially with SETD2 by matching the distinct transition-state features of SETD2鈥檚 catalytically active conformer. With Pr-SNF as a structure probe, we further revealed the dual roles of SETD2鈥檚 post-SET loop in regulating substrate access through a distinct topological reconfiguration. Privileged sinefungin scaffolds are expected to have broad use as structure and chemical probes of methyltransferases.