Structural snapshots of human HDAC8 provide insights into the class I histone deacetylases.
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.
Somoza
John R
JR
Celera, 180 Kimball Way, South San Francisco, CA 94080 USA. john.somoza@celera.com
Skene
Robert J
RJ
Katz
Bradley A
BA
Mol
Clifford
C
Ho
Joseph D
JD
Jennings
Andy J
AJ
Luong
Christine
C
Arvai
Andrew
A
Buggy
Joseph J
JJ
Chi
Ellen
E
Tang
Jie
J
Sang
Bi-Ching
BC
Verner
Erik
E
Wynands
Robert
R
Leahy
Ellen M
EM
Dougan
Douglas R
DR
Snell
Gyorgy
G
Navre
Marc
M
Knuth
Mark W
MW
Swanson
Ronald V
RV
McRee
Duncan E
DE
Tari
Leslie W
LW
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
D012097:Repressor Proteins; C409470:HDAC8 protein, human; D006655:Histone Deacetylases