5icn
From Proteopedia
HDAC1:MTA1 in complex with inositol-6-phosphate and a novel peptide inhibitor based on histone H4
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. [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.[1] [2] [3] [4] [5] [6] Publication Abstract from PubMedHistone 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[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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Categories: Histone deacetylase | Human | Large Structures | Synthetic construct sequences | Jameson, A G | Millard, C J | Robertson, N S | Schwabe, J W.R | Watson, P J | Ip6 | Metastasis associated protein | Transcription | Transcription repression inositol phosphate corepressor histone deacetylase hdac1 hdac3 histone
