5Z2T

Crystal structure of DNA-bound DUX4-HD2

Summary for 5Z2T

• Entry DOI: 10.2210/pdb5z2t/pdb
• Descriptor: Double homeobox protein 4, 5'-D(*TP*TP*CP*TP*AP*AP*TP*CP*TP*AP*AP*TP*CP*TP*T)-3', 5'-D(P*AP*AP*GP*AP*TP*TP*AP*GP*AP*TP*TP*AP*GP*T)-3', ... (4 entities in total)
• Functional Keywords: acute lymphoblastic leukemia, dux4/igh, dux4-responsive-element, transactivation, ergalt, dna binding protein-dna complex, dna binding protein/dna
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 23424.41

Authors

Dong, X.,Zhang, W.,Wu, H.,Huang, J.,Zhang, M.,Wang, P.,Zhang, H.,Chen, Z.,Chen, S.,Meng, G. (deposition date: 2018-01-04, release date: 2018-04-04, Last modification date: 2023-11-22)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.623 Å)