title: Structural snapshots of human HDAC8 provide insights into the class I histone deacetylases.
abstract: Modulation of the acetylation state of histones plays a pivotal role in the regulation of gene expression. Histone deacetylases (HDACs) catalyze the removal of acetyl groups from lysines near the N termini of histones. This reaction promotes the condensation of chromatin, leading to repression of transcription. HDAC deregulation has been linked to several types of cancer, suggesting a potential use for HDAC inhibitors in oncology. Here we describe the first crystal structures of a human HDAC: the structures of human HDAC8 complexed with four structurally diverse hydroxamate inhibitors. This work sheds light on the catalytic mechanism of the HDACs, and on differences in substrate specificity across the HDAC family. The structure also suggests how phosphorylation of Ser39 affects HDAC8 activity.
authors.affiliation: Celera, 180 Kimball Way, South San Francisco, CA 94080 USA. john.somoza@celera.com
authors.forename: John R
authors.initials: JR
authors.lastname: Somoza
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Skene
authors.forename: Bradley A
authors.initials: BA
authors.lastname: Katz
authors.forename: Clifford
authors.initials: C
authors.lastname: Mol
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Ho
authors.forename: Andy J
authors.initials: AJ
authors.lastname: Jennings
authors.forename: Christine
authors.initials: C
authors.lastname: Luong
authors.forename: Andrew
authors.initials: A
authors.lastname: Arvai
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Buggy
authors.forename: Ellen
authors.initials: E
authors.lastname: Chi
authors.forename: Jie
authors.initials: J
authors.lastname: Tang
authors.forename: Bi-Ching
authors.initials: BC
authors.lastname: Sang
authors.forename: Erik
authors.initials: E
authors.lastname: Verner
authors.forename: Robert
authors.initials: R
authors.lastname: Wynands
authors.forename: Ellen M
authors.initials: EM
authors.lastname: Leahy
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Dougan
authors.forename: Gyorgy
authors.initials: G
authors.lastname: Snell
authors.forename: Marc
authors.initials: M
authors.lastname: Navre
authors.forename: Mark W
authors.initials: MW
authors.lastname: Knuth
authors.forename: Ronald V
authors.initials: RV
authors.lastname: Swanson
authors.forename: Duncan E
authors.initials: DE
authors.lastname: McRee
authors.forename: Leslie W
authors.initials: LW
authors.lastname: Tari
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006655:Histone Deacetylases / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D011487:Protein Conformation; D012097:Repressor Proteins / Q000737:chemistry* / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D012097:Repressor Proteins; C409470:HDAC8 protein, human; D006655:Histone Deacetylases