7EYI

Crystal structure of ZBTB7A in complex with gamma-globin -200 sequence element with C-194A mutation

Summary for 7EYI

• Entry DOI: 10.2210/pdb7eyi/pdb
• Descriptor: Zinc finger and BTB domain-containing protein 7A, DNA (5'-D(*AP*TP*AP*GP*GP*GP*CP*CP*CP*CP*TP*TP*CP*CP*CP*AP*AP*C)-3'), DNA (5'-D(*TP*GP*TP*TP*GP*GP*GP*AP*AP*GP*GP*GP*GP*CP*CP*CP*TP*A)-3'), ... (6 entities in total)
• Functional Keywords: zbtb7a, gamma-globin, -200 cluste., structural protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 6
• Total formula weight: 52876.80

Authors

Yang, Y.,Shi, Y.Y. (deposition date: 2021-05-31, release date: 2021-09-01, Last modification date: 2024-05-29)

Primary citation

Yang, Y.,Ren, R.,Ly, L.C.,Horton, J.R.,Li, F.,Quinlan, K.G.R.,Crossley, M.,Shi, Y.,Cheng, X.
Structural basis for human ZBTB7A action at the fetal globin promoter.
Cell Rep, 36:109759-109759, 2021

PubMed Abstract: Elevated levels of fetal globin protect against β-hemoglobinopathies, such as sickle cell disease and β-thalassemia. Two zinc-finger (ZF) repressors, BCL11A and ZBTB7A/LRF, bind directly to the fetal globin promoter elements positioned at -115 and -200, respectively. Here, we describe X-ray structures of the ZBTB7A DNA-binding domain, consisting of four adjacent ZFs, in complex with the -200 sequence element, which contains two copies of four consecutive C:G base pairs. ZF1 and ZF2 recognize the 5' C:G quadruple, and ZF4 contacts the 3' C:G quadruple. Natural non-coding DNA mutations associated with hereditary persistence of fetal hemoglobin (HPFH) impair ZBTB7A DNA binding, with the most severe disruptions resulting from mutations in the base pairs recognized by ZF1 and ZF2. Our results firmly establish ZBTB7A/LRF as a key molecular regulator of fetal globin expression and inform genome-editing strategies that inhibit repressor binding and boost fetal globin expression to treat hemoglobinopathies.

PubMed: 34592153
DOI: 10.1016/j.celrep.2021.109759

Experimental method

X-RAY DIFFRACTION (2.401 Å)