Summary information and primary citation
- PDB-id
- 5z2t; SNAP-derived features in text and JSON formats;
DNAproDB
- Class
- DNA binding protein-DNA
- Method
- X-ray (2.623 Å)
- Summary
- Crystal structure of DNA-bound dux4-hd2
- Reference
- Dong X, Zhang W, Wu H, Huang J, Zhang M, Wang P, Zhang H, Chen Z, Chen SJ, Meng G (2018): "Structural basis of DUX4/IGH-driven transactivation." Leukemia, 32, 1466-1476. doi: 10.1038/s41375-018-0093-1.
- 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 ERGaltthrough 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 DNADRE-bound DUX4HD2and 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.
