SNAP output for PDB entry 8tlo [SNAP web server]

PDB-id

8tlo; SNAP-derived features in text and JSON formats; DNAproDB

Class

transcription

Method

X-ray (2.76 Å)

Summary

Crystal structure analysis of bcl11a in complex with DNA

Reference

Viennet T, Yin M, Jayaraj A, Kim W, Sun ZJ, Fujiwara Y, Zhang K, Seruggia D, Seo HS, Dhe-Paganon S, Orkin SH, Arthanari H (2024): "Structural insights into the DNA-binding mechanism of BCL11A: The integral role of ZnF6." Structure. doi: 10.1016/j.str.2024.09.022.

Abstract

The transcription factor BCL11A is a critical regulator of the switch from fetal hemoglobin (HbF: α₂γ₂) to adult hemoglobin (HbA: α₂β₂) during development. BCL11A binds at a cognate recognition site (TGACCA) in the γ-globin gene promoter and represses its expression. DNA-binding is mediated by a triple zinc finger domain, designated ZnF456. Here, we report comprehensive investigation of ZnF456, leveraging X-ray crystallography and NMR to determine the structures in both the presence and absence of DNA. We delve into the dynamics and mode of interaction with DNA. Moreover, we discovered that the last zinc finger of BCL11A (ZnF6) plays a different role compared to ZnF4 and 5, providing a positive entropic contribution to DNA binding and γ-globin gene repression. Comprehending the DNA binding mechanism of BCL11A opens avenues for the strategic, structure-based design of novel therapeutics targeting sickle cell disease and β-thalassemia.