7jvw | pdb_00007jvw
Crystal structure of human histone deacetylase 8 (HDAC8) G320R mutation complexed with M344
Structural highlights
FunctionHDAC8_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. May play a role in smooth muscle cell contractility.[1] [2] [3] [4] Publication Abstract from PubMedCornelia de Lange Syndrome (CdLS) and associated spectrum disorders are characterized by one or more congenital anomalies including distinctive facial features, upper limb abnormalities, intellectual disability, and other symptoms. The molecular genetic basis of CdLS is linked to defects in cohesin, a protein complex that functions in sister chromatid cohesion, chromatin organization, and transcriptional regulation. Histone deacetylase 8 (HDAC8) plays an important role in cohesin function by catalyzing the deacetylation of SMC3, which is required for efficient recycling of the cohesin complex. Missense mutations in HDAC8 have been identified in children diagnosed with CdLS spectrum disorders, and here we outline structure-function relationships for four of these mutations. Specifically, we report the 1.50 A-resolution structure of the I45T HDAC8-suberoylanilide hydroxamic acid complex, the 1.84 A-resolution structure of E66D/Y306F HDAC8 complexed with a peptide assay substrate, and the 2.40 A-resolution structure of G320R HDAC8 complexed with the inhibitor M344. Additionally, we present a computationally generated model of D176G HDAC8. These structures illuminate new structure-function relationships for HDAC8 and highlight the importance of long-range interactions in the protein scaffold that can influence catalytic function. Structural analysis of histone deacetylase 8 mutants associated with Cornelia de Lange Syndrome spectrum disorders.,Osko JD, Porter NJ, Decroos C, Lee MS, Watson PR, Raible SE, Krantz ID, Deardorff MA, Christianson DW J Struct Biol. 2020 Dec 11;213(1):107681. doi: 10.1016/j.jsb.2020.107681. PMID:33316326[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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