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| | ==HDAC1:MTA1 in complex with inositol-6-phosphate and a novel peptide inhibitor based on histone H4== | | ==HDAC1:MTA1 in complex with inositol-6-phosphate and a novel peptide inhibitor based on histone H4== |
| - | <StructureSection load='5icn' size='340' side='right' caption='[[5icn]], [[Resolution|resolution]] 3.30Å' scene=''> | + | <StructureSection load='5icn' size='340' side='right'caption='[[5icn]], [[Resolution|resolution]] 3.30Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5icn]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5ICN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5ICN FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5icn]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5ICN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5ICN FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=I6P:INOSITOL+1,2,3,4,5,6-HEXAKISPHOSPHATE'>I6P</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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]] 3.3Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=6A0:(2S)-2-AMINO-8-(HYDROXYAMINO)-8-OXOOCTANOIC+ACID'>6A0</scene></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6A0:(2S)-2-AMINO-8-(HYDROXYAMINO)-8-OXOOCTANOIC+ACID'>6A0</scene>, <scene name='pdbligand=IHP:INOSITOL+HEXAKISPHOSPHATE'>IHP</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Histone_deacetylase Histone deacetylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.1.98 3.5.1.98] </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=5icn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5icn OCA], [https://pdbe.org/5icn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5icn RCSB], [https://www.ebi.ac.uk/pdbsum/5icn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5icn ProSAT]</span></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=5icn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5icn OCA], [http://pdbe.org/5icn PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5icn RCSB], [http://www.ebi.ac.uk/pdbsum/5icn PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5icn ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/MTA1_HUMAN MTA1_HUMAN]] May be involved in the regulation of gene expression by covalent modification of histone proteins. Isoform Long is a corepressor of estrogen receptor (ER). Isoform Short binds to ER and sequesters it in the cytoplasm and enhances non-genomic responses of ER. [[http://www.uniprot.org/uniprot/HDAC1_HUMAN HDAC1_HUMAN]] Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Deacetylates SP proteins, SP1 and SP3, and regulates their function. Component of the BRG1-RB1-HDAC1 complex, which negatively regulates the CREST-mediated transcription in resting neurons. Upon calcium stimulation, HDAC1 is released from the complex and CREBBP is recruited, which facilitates transcriptional activation. Deacetylates TSHZ3 and regulates its transcriptional repressor activity. Deacetylates 'Lys-310' in RELA and thereby inhibits the transcriptional activity of NF-kappa-B. Component a RCOR/GFI/KDM1A/HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development.<ref>PMID:12837748</ref> <ref>PMID:16478997</ref> <ref>PMID:17000776</ref> <ref>PMID:17704056</ref> <ref>PMID:19081374</ref> <ref>PMID:19343227</ref> | + | [https://www.uniprot.org/uniprot/MTA1_HUMAN MTA1_HUMAN] May be involved in the regulation of gene expression by covalent modification of histone proteins. Isoform Long is a corepressor of estrogen receptor (ER). Isoform Short binds to ER and sequesters it in the cytoplasm and enhances non-genomic responses of ER. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | ==See Also== | | ==See Also== |
| - | *[[Histone deacetylase|Histone deacetylase]] | + | *[[Histone deacetylase 3D structures|Histone deacetylase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Histone deacetylase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Jameson, A G]] | + | [[Category: Large Structures]] |
| - | [[Category: Millard, C J]] | + | [[Category: Synthetic construct]] |
| - | [[Category: Robertson, N S]] | + | [[Category: Jameson AG]] |
| - | [[Category: Schwabe, J W.R]] | + | [[Category: Millard CJ]] |
| - | [[Category: Watson, P J]] | + | [[Category: Robertson NS]] |
| - | [[Category: Ip6]] | + | [[Category: Schwabe JWR]] |
| - | [[Category: Metastasis associated protein]] | + | [[Category: Watson PJ]] |
| - | [[Category: Transcription]]
| + | |
| - | [[Category: Transcription repression inositol phosphate corepressor histone deacetylase hdac1 hdac3 histone]]
| + | |
| Structural highlights
Function
MTA1_HUMAN May be involved in the regulation of gene expression by covalent modification of histone proteins. Isoform Long is a corepressor of estrogen receptor (ER). Isoform Short binds to ER and sequesters it in the cytoplasm and enhances non-genomic responses of ER.
Publication Abstract from PubMed
Histone deacetylases (HDACs) 1, 2 and 3 form the catalytic subunit of several large transcriptional repression complexes. Unexpectedly, the enzymatic activity of HDACs in these complexes has been shown to be regulated by inositol phosphates, which bind in a pocket sandwiched between the HDAC and co-repressor proteins. However, the actual mechanism of activation remains poorly understood. Here we have elucidated the stereochemical requirements for binding and activation by inositol phosphates, demonstrating that activation requires three adjacent phosphate groups and that other positions on the inositol ring can tolerate bulky substituents. We also demonstrate that there is allosteric communication between the inositol-binding site and the active site. The crystal structure of the HDAC1:MTA1 complex bound to a novel peptide-based inhibitor and to inositol hexaphosphate suggests a molecular basis of substrate recognition, and an entropically driven allosteric mechanism of activation.
Insights into the activation mechanism of class I HDAC complexes by inositol phosphates.,Watson PJ, Millard CJ, Riley AM, Robertson NS, Wright LC, Godage HY, Cowley SM, Jamieson AG, Potter BV, Schwabe JW Nat Commun. 2016 Apr 25;7:11262. doi: 10.1038/ncomms11262. PMID:27109927[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Watson PJ, Millard CJ, Riley AM, Robertson NS, Wright LC, Godage HY, Cowley SM, Jamieson AG, Potter BV, Schwabe JW. Insights into the activation mechanism of class I HDAC complexes by inositol phosphates. Nat Commun. 2016 Apr 25;7:11262. doi: 10.1038/ncomms11262. PMID:27109927 doi:http://dx.doi.org/10.1038/ncomms11262
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