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7eyi

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

Structural highlights

7eyi is a 6 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.401Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

ZBT7A_HUMAN Plays a key role in the instruction of early lymphoid progenitors to develop into B lineage by repressing T-cell instructive Notch signals (By similarity). Specifically represses the transcription of the CDKN2A gene. Efficiently abrogates E2F1-dependent CDKN2A transactivation/de-repression. Binds to the consensus sequence 5'-[GA][CA]GACCCCCCCCC-3' (By similarity).

Publication Abstract from PubMed

Elevated levels of fetal globin protect against beta-hemoglobinopathies, such as sickle cell disease and beta-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.

Structural basis for human ZBTB7A action at the fetal globin promoter.,Yang Y, Ren R, Ly LC, Horton JR, Li F, Quinlan KGR, Crossley M, Shi Y, Cheng X Cell Rep. 2021 Sep 28;36(13):109759. doi: 10.1016/j.celrep.2021.109759. PMID:34592153^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Yang Y, Ren R, Ly LC, Horton JR, Li F, Quinlan KGR, Crossley M, Shi Y, Cheng X. Structural basis for human ZBTB7A action at the fetal globin promoter. Cell Rep. 2021 Sep 28;36(13):109759. PMID:34592153 doi:10.1016/j.celrep.2021.109759