3PDN

Crystal structure of SmyD3 in complex with methyltransferase inhibitor sinefungin

3PDN の概要

• エントリーDOI: 10.2210/pdb3pdn/pdb
• 分子名称: SET and MYND domain-containing protein 3, SINEFUNGIN, GLYCEROL, ... (6 entities in total)
• 機能のキーワード: rossmann fold, zinc finger, methyltransferase, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: Q9H7B4
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 50356.91

構造登録者

Sirinupong, N.,Brunzelle, J.,Yang, Z. (登録日: 2010-10-23, 公開日: 2010-11-17, 最終更新日: 2024-02-21)

主引用文献

Sirinupong, N.,Brunzelle, J.,Doko, E.,Yang, Z.
Structural Insights into the Autoinhibition and Posttranslational Activation of Histone Methyltransferase SmyD3.
J.Mol.Biol., 406:149-159, 2011

PubMed Abstract: The SmyD family represents a new class of chromatin regulators that is important in heart and skeletal muscle development. However, the critical questions regarding how they are regulated posttranslationally remain largely unknown. We previously suggested that the histone methyltransferase activity of SmyD1, a vital myogenic regulator, appears to be regulated by autoinhibition and that the possible hinge motion of the conserved C-terminal domain (CTD) might be central to the maintenance and release of the autoinhibition. However, the lack of direct evidence of the hinge motion has limited our further understanding of this autoinhibitory mechanism. Here, we report the crystal structure of full-length SmyD3 in complex with the methyltransferase inhibitor sinefungin at 1.7 Å. SmyD3 has a two-lobed structure with the substrate binding cleft located at the bottom of a  15-Å-deep crevice formed between the N- and C-terminal lobes. Comparison of SmyD3 and SmyD1 clearly suggests that the CTD can undergo a large hinge-bending motion that defines two distinct conformations: SmyD3 adopts a closed conformation with the CTD partially blocking the substrate binding cleft; in contrast, SmyD1 appears to represent an open form, where the CTD swings out by ∼12 Å from the N-terminal lobe, forming an open cleft with the active site completely exposed. Overall, these findings provide novel structural insights into the mechanism that modulates the activity of the SmyD proteins and support the observation that a posttranslational activation, such as by molecular chaperon Hsp90, is required to potentiate the proteins.

PubMed: 21167177
DOI: 10.1016/j.jmb.2010.12.014

実験手法

X-RAY DIFFRACTION (1.7 Å)