6whn

Histone deacetylases complex with peptide macrocycles

spinqualitylabelsall models 6whn, resolution 1.54Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6whn is a 6 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.54Å Ligands: DLY, NA, NHE, PEG, PG4, PGE, U2M, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function HDAC2_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. Forms transcriptional repressor complexes by associating with MAD, SIN3, YY1 and N-COR. Interacts in the late S-phase of DNA-replication with DNMT1 in the other transcriptional repressor complex composed of DNMT1, DMAP1, PCNA, CAF1. Deacetylates TSHZ3 and regulates its transcriptional repressor activity. Component of a RCOR/GFI/KDM1A/HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development. Publication Abstract from PubMed Despite recent success in computational design of structured cyclic peptides, de novo design of cyclic peptides that bind to any protein functional site remains difficult. To address this challenge, we develop a computational "anchor extension" methodology for targeting protein interfaces by extending a peptide chain around a non-canonical amino acid residue anchor. To test our approach using a well characterized model system, we design cyclic peptides that inhibit histone deacetylases 2 and 6 (HDAC2 and HDAC6) with enhanced potency compared to the original anchor (IC(50) values of 9.1 and 4.4 nM for the best binders compared to 5.4 and 0.6 microM for the anchor, respectively). The HDAC6 inhibitor is among the most potent reported so far. These results highlight the potential for de novo design of high-affinity protein-peptide interfaces, as well as the challenges that remain. Anchor extension: a structure-guided approach to design cyclic peptides targeting enzyme active sites.,Hosseinzadeh P, Watson PR, Craven TW, Li X, Rettie S, Pardo-Avila F, Bera AK, Mulligan VK, Lu P, Ford AS, Weitzner BD, Stewart LJ, Moyer AP, Di Piazza M, Whalen JG, Greisen PJ, Christianson DW, Baker D Nat Commun. 2021 Jun 7;12(1):3384. doi: 10.1038/s41467-021-23609-8. PMID:34099674 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Histone deacetylase 3D structures

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