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| | ==Crystal structure of the bromodomain of human ATAD2 with a disulfide bridge== | | ==Crystal structure of the bromodomain of human ATAD2 with a disulfide bridge== |
| - | <StructureSection load='6cps' size='340' side='right' caption='[[6cps]], [[Resolution|resolution]] 1.93Å' scene=''> | + | <StructureSection load='6cps' size='340' side='right'caption='[[6cps]], [[Resolution|resolution]] 1.93Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6cps]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CPS OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6CPS FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6cps]] is a 1 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=6CPS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6CPS FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EPE:4-(2-HYDROXYETHYL)-1-PIPERAZINE+ETHANESULFONIC+ACID'>EPE</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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]] 1.93Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ATAD2, L16, PRO2000 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EPE:4-(2-HYDROXYETHYL)-1-PIPERAZINE+ETHANESULFONIC+ACID'>EPE</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6cps FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6cps OCA], [http://pdbe.org/6cps PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6cps RCSB], [http://www.ebi.ac.uk/pdbsum/6cps PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6cps ProSAT]</span></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=6cps FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6cps OCA], [https://pdbe.org/6cps PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6cps RCSB], [https://www.ebi.ac.uk/pdbsum/6cps PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6cps ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/ATAD2_HUMAN ATAD2_HUMAN]] May be a transcriptional coactivator of the nuclear receptor ESR1 required to induce the expression of a subset of estradiol target genes, such as CCND1, MYC and E2F1. May play a role in the recruitment or occupancy of CREBBP at some ESR1 target gene promoters. May be required for histone hyperacetylation. Involved in the estrogen-induced cell proliferation and cell cycle progression of breast cancer cells.<ref>PMID:17998543</ref> | + | [https://www.uniprot.org/uniprot/ATAD2_HUMAN ATAD2_HUMAN] May be a transcriptional coactivator of the nuclear receptor ESR1 required to induce the expression of a subset of estradiol target genes, such as CCND1, MYC and E2F1. May play a role in the recruitment or occupancy of CREBBP at some ESR1 target gene promoters. May be required for histone hyperacetylation. Involved in the estrogen-induced cell proliferation and cell cycle progression of breast cancer cells.<ref>PMID:17998543</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 6cps" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6cps" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[ATPase family AAA domain-containing protein|ATPase family AAA domain-containing protein]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Carlson, S]] | + | [[Category: Large Structures]] |
| - | [[Category: Eckenroth, B E]] | + | [[Category: Carlson S]] |
| - | [[Category: Glass, K C]] | + | [[Category: Eckenroth BE]] |
| - | [[Category: Bromodomain]] | + | [[Category: Glass KC]] |
| - | [[Category: Chromatin reader domain]]
| + | |
| - | [[Category: Disulfide bridge]]
| + | |
| - | [[Category: Epigenetic]]
| + | |
| - | [[Category: Protein binding]]
| + | |
| Structural highlights
Function
ATAD2_HUMAN May be a transcriptional coactivator of the nuclear receptor ESR1 required to induce the expression of a subset of estradiol target genes, such as CCND1, MYC and E2F1. May play a role in the recruitment or occupancy of CREBBP at some ESR1 target gene promoters. May be required for histone hyperacetylation. Involved in the estrogen-induced cell proliferation and cell cycle progression of breast cancer cells.[1]
Publication Abstract from PubMed
The ATPase Family, AAA domain-containing protein 2 (ATAD2) contains a C-terminal bromodomain, which functions as a chromatin reader domain recognizing acetylated lysine on the histone tails within the nucleosome. ATAD2 is overexpressed in many cancers and its expression is correlated with poor patient outcomes, making it an attractive therapeutic target and potential biomarker. We solved the crystal structure of the ATAD2 bromodomain and found that it contains a disulfide bridge near the base of the acetyllysine binding pocket (Cys1057-Cys1079). Site-directed mutagenesis revealed that removal of a free C-terminal cysteine (C1101) residue greatly improved the solubility of the ATAD2 bromodomain in vitro. Isothermal titration calorimetry experiments in combination with the Ellman's assay demonstrated that formation of an intramolecular disulfide bridge negatively impacts the ligand binding affinities and alters the thermodynamic parameters of the ATAD2 bromodomain interaction with a histone H4K5ac peptide as well as a small molecule bromodomain ligand. Molecular dynamics simulations indicate that the formation of the disulfide bridge in the ATAD2 bromodomain does not alter the structure of the folded state or flexibility of the acetyllysine binding pocket. However, consideration of this unique structural feature should be taken into account when examining ligand-binding affinity, or in the design of new bromodomain inhibitor compounds that interact with this acetyllysine reader module. This article is protected by copyright. All rights reserved.
Disulfide bridge formation influences ligand recognition by the ATAD2 bromodomain.,Gay JC, Eckenroth BE, Evans CM, Langini C, Carlson S, Lloyd JT, Caflisch A, Glass KC Proteins. 2018 Dec 6. doi: 10.1002/prot.25636. PMID:30520161[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Zou JX, Revenko AS, Li LB, Gemo AT, Chen HW. ANCCA, an estrogen-regulated AAA+ ATPase coactivator for ERalpha, is required for coregulator occupancy and chromatin modification. Proc Natl Acad Sci U S A. 2007 Nov 13;104(46):18067-72. Epub 2007 Nov 12. PMID:17998543 doi:http://dx.doi.org/10.1073/pnas.0705814104
- ↑ Gay JC, Eckenroth BE, Evans CM, Langini C, Carlson S, Lloyd JT, Caflisch A, Glass KC. Disulfide bridge formation influences ligand recognition by the ATAD2 bromodomain. Proteins. 2018 Dec 6. doi: 10.1002/prot.25636. PMID:30520161 doi:http://dx.doi.org/10.1002/prot.25636
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