5Z2S

Crystal structure of DUX4-HD2 domain

5Z2S の概要

• エントリーDOI: 10.2210/pdb5z2s/pdb
• 分子名称: Double homeobox protein 4 (2 entities in total)
• 機能のキーワード: acute lymphoblastic leukemia, dux4/igh, dux4-responsive-element, transactivation, ergalt, dna binding protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 6285.15

構造登録者

Dong, X.,Zhang, W.,Wu, H.,Huang, J.,Zhang, M.,Wang, P.,Zhang, H.,Chen, Z.,Chen, S.,Meng, G. (登録日: 2018-01-03, 公開日: 2018-04-04, 最終更新日: 2023-11-22)

主引用文献

Dong, X.,Zhang, W.,Wu, H.,Huang, J.,Zhang, M.,Wang, P.,Zhang, H.,Chen, Z.,Chen, S.J.,Meng, G.
Structural basis of DUX4/IGH-driven transactivation.
Leukemia, 32:1466-1476, 2018

PubMed Abstract: Oncogenic fusions are major drivers in leukemogenesis and may serve as potent targets for treatment. DUX4/IGHs have been shown to trigger the abnormal expression of ERG through binding to DUX4-Responsive-Element (DRE), which leads to B-cell differentiation arrest and a full-fledged B-ALL. Here, we determined the crystal structures of Apo- and DNA-bound DUX4 and revealed a clamp-like transactivation mechanism via the double homeobox domain. Biophysical characterization showed that mutations in the interacting interfaces significantly impaired the DNA binding affinity of DUX4 homeobox. These mutations, when introduced into DUX4/IGH, abrogated its transactivation activity in Reh cells. More importantly, the structure-based mutants significantly impaired the inhibitory effects of DUX4/IGH upon B-cell differentiation in mouse progenitor cells. All these results help to define a key DUX4/IGH-DRE recognition/step in B-ALL.

PubMed: 29572508
DOI: 10.1038/s41375-018-0093-1

実験手法

X-RAY DIFFRACTION (1.5 Å)