SNAP annotations: PDB entry 12un

PDB-id

12un; DSSR-derived features in text and JSON formats; DNAproDB

Class

DNA binding protein-DNA

Method

X-ray (3.03 Å)

Summary

Bcl11b zf2-3 in complex with a DNA sequence observed in the human globin locus containing motif tggcca (oligo 4-3)-p212121 form

Reference

Lee J, Zhou J, Horton JR, Yu M, Muoghalu MD, Khan FA, Zhang X, Huang Y, Blumenthal RM, Zhang X, Cheng X (2026): "Bipartite DNA binding domain of transcription factor BCL11B binds clustered short DNA sequence motifs." Biorxiv. doi: 10.64898/2026.05.01.721897.

Abstract

B-cell leukemia/lymphoma 11B (BCL11B), despite its name, is a key regulator of T-cell development, specification, and T-cell malignancies. BCL11B contains a bipartite DNA binding domain composed of two C2H2 zinc finger arrays: low-affinity ZF2-3 and high affinity ZF4-6. These arrays function as homotypic modules that recognize similar six-nucleotide motifs, TG(N)CC(C/T/A), as seven of the eight DNA base-contacting residues are conserved between them. The most conserved interactions involve GG dinucleotides, contacted by arginine and lysine residues at key base-interacting positions in ZF3 and ZF5. The two ZF arrays are connected by a long ~300-residue linker that provides flexibility in how the arrays engage DNA, allowing ZF2-3 and ZF4-6 binding to the same or opposite strands with variable orientation, spacing and positioning along the DNA. This extended linker is enriched in serine/threonine, acidic residues (aspartate/glutamate), and structural residues (glycine/proline), providing additional layers of transcriptional regulation possibly through post-translational modification, electrostatic modulation, and/or condensate formation. We also examined six missense mutations in base-interacting residues, that are associated with neurodevelopmental disorders. Substitutions replacing bulky, positively charged arginine or lysine with smaller or hydrophobic residues likely reduce DNA-binding affinity and/or specificity, whereas substitutions between asparagine and lysine may alter base recognition preferences.