8TLO

Crystal Structure Analysis of BCL11A in complex with DNA

Summary for 8TLO

• Entry DOI: 10.2210/pdb8tlo/pdb
• Descriptor: B-cell lymphoma/leukemia 11A, DNA (5'-D(P*CP*GP*AP*CP*CP*GP*CP*AP*TP*TP*GP*GP*TP*CP*AP*AP*GP*CP*G)-3'), DNA (5'-D(P*GP*CP*TP*TP*GP*AP*CP*CP*AP*AP*TP*GP*CP*GP*GP*TP*CP*GP*C)-3'), ... (4 entities in total)
• Functional Keywords: transcription factor, dna-binding, zn finger, transcription-dna complex, transcription
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 24600.45

Authors

Seo, H.-S.,Dhe-Paganon, S. (deposition date: 2023-07-27, release date: 2024-08-14, Last modification date: 2024-12-18)

Primary citation

Viennet, T.,Yin, M.,Jayaraj, A.,Kim, W.,Sun, Z.J.,Fujiwara, Y.,Zhang, K.,Seruggia, D.,Seo, H.S.,Dhe-Paganon, S.,Orkin, S.H.,Arthanari, H.
Structural insights into the DNA-binding mechanism of BCL11A: The integral role of ZnF6.
Structure, 32:2276-2286.e4, 2024

PubMed Abstract: The transcription factor BCL11A is a critical regulator of the switch from fetal hemoglobin (HbF: αγ) to adult hemoglobin (HbA: αβ) 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.

PubMed: 39423807
DOI: 10.1016/j.str.2024.09.022

Experimental method

X-RAY DIFFRACTION (2.76 Å)