7n5t: Difference between revisions
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==== | ==ZBTB7A Zinc Finger Domain Bound to -200 Site of Fetal Globin Promoter (Oligo 5)== | ||
<StructureSection load='7n5t' size='340' side='right'caption='[[7n5t]]' scene=''> | <StructureSection load='7n5t' size='340' side='right'caption='[[7n5t]], [[Resolution|resolution]] 2.90Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id= OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol= FirstGlance]. <br> | <table><tr><td colspan='2'>[[7n5t]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7N5T OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7N5T FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7n5t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7n5t OCA], [https://pdbe.org/7n5t PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7n5t RCSB], [https://www.ebi.ac.uk/pdbsum/7n5t PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7n5t ProSAT]</span></td></tr> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.9Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7n5t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7n5t OCA], [https://pdbe.org/7n5t PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7n5t RCSB], [https://www.ebi.ac.uk/pdbsum/7n5t PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7n5t ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[https://www.uniprot.org/uniprot/ZBT7A_HUMAN 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). | |||
<div style="background-color:#fffaf0;"> | |||
== 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<ref>PMID:34592153</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7n5t" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: | [[Category: Cheng X]] | ||
[[Category: Horton JR]] | |||
[[Category: Ren R]] | |||
Latest revision as of 19:24, 18 October 2023
ZBTB7A Zinc Finger Domain Bound to -200 Site of Fetal Globin Promoter (Oligo 5)ZBTB7A Zinc Finger Domain Bound to -200 Site of Fetal Globin Promoter (Oligo 5)
Structural highlights
FunctionZBT7A_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 PubMedElevated 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
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