SNAP output for PDB entry 5z2t [SNAP web server]

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 ERG_alt 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_DRE-bound DUX4_HD2 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.