1W22

Crystal structure of inhibited human HDAC8

Summary for 1W22

• Entry DOI: 10.2210/pdb1w22/pdb
• Related: 1T64 1T67 1T69 1VKG
• Descriptor: HISTONE DEACETYLASE 8, ZINC ION, POTASSIUM ION, ... (5 entities in total)
• Functional Keywords: hydroxamic acid, chromatin, deacetylation, hdac, hydrolase, nuclear protein, repressor
• Biological source: HOMO SAPIENS
• Cellular location: Nucleus: Q9BY41
• Total number of polymer chains: 2
• Total formula weight: 84671.06

Authors

Vannini, A.,Volpari, C.,Caroli Casavola, E.,Di Marco, S. (deposition date: 2004-06-25, release date: 2004-09-24, Last modification date: 2023-12-13)

Primary citation

Vannini, A.,Volpari, C.,Filocamo, G.,Caroli Casavola, E.,Brunetti, M.,Renzoni, D.,Chakravarty, P.,Paolini, C.,De Francesco, R.,Gallinari, P.,Steinckuhler, C.,Di Marco, S.
Crystal Structure of a Eukaryotic Zn-Dependent Histone Deacetylase,Human Hdac8,Complexed with a Hydroxamic Acid Inhibitor
Proc.Natl.Acad.Sci.USA, 101:15064-, 2004

PubMed Abstract: Histone deacetylases (HDACs) are a family of enzymes involved in the regulation of gene expression, DNA repair, and stress response. These processes often are altered in tumors, and HDAC inhibitors have had pronounced antitumor activity with promising results in clinical trials. Here, we report the crystal structure of human HDAC8 in complex with a hydroxamic acid inhibitor. Such a structure of a eukaryotic zinc-dependent HDAC has not be described previously. Similar to bacterial HDAC-like protein, HDAC8 folds in a single alpha/beta domain. The inhibitor and the zinc-binding sites are similar in both proteins. However, significant differences are observed in the length and structure of the loops surrounding the active site, including the presence of two potassium ions in HDAC8 structure, one of which interacts with key catalytic residues. CD data suggest a direct role of potassium in the fold stabilization of HDAC8. Knockdown of HDAC8 by RNA interference inhibits growth of human lung, colon, and cervical cancer cell lines, highlighting the importance of this HDAC subtype for tumor cell proliferation. Our findings open the way for the design and development of selective inhibitors of HDAC8 as possible antitumor agents.

PubMed: 15477595
DOI: 10.1073/PNAS.0404603101

Experimental method

X-RAY DIFFRACTION (2.5 Å)