SNAP annotations: PDB entry 12uq

PDB-id

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

Class

DNA binding protein-DNA

Method

X-ray (3.29 Å)

Summary

Bcl11b zf2-3 in complex with a DNA sequence containing two binding sites (motifs tgtccc and tggcct)

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.