Crystal Structure of a Bacterial Class 2 Histone Deacetylase Homologue

• Published in: Journal of molecular biology Vol. 354; no. 1; pp. 107 - 120
• Main Authors: Nielsen, Tine Kragh, Hildmann, Christian, Dickmanns, Achim, Schwienhorst, Andreas, Ficner, Ralf
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 18.11.2005
• Subjects: Acetates - chemistry; Alcaligenes; amidohydrolase; Amidohydrolases - chemistry; Amino Acid Sequence; Bacteria; Binding Sites; Bordetella; Bordetella - enzymology; Catalytic Domain; Crystallography, X-Ray; histone deacetylase; Histone Deacetylases - chemistry; Hydroxamic Acids - chemistry; Models, Molecular; Molecular Sequence Data; Protein Conformation; SAHA; Sequence Homology, Amino Acid; X-ray crystallography; Zinc; zinc ion; X-ray crystallography; amidohydrolase; SAHA; HDAH; SAD; zinc ion; histone deacetylase; HDAC
• ISSN: 0022-2836; 1089-8638
• DOI: 10.1016/j.jmb.2005.09.065

Histone deacetylases (HDACs) are among the most promising targets in cancer therapy. However, structural information greatly enhancing the design of HDAC inhibitors as novel chemotherapeutics has not been available on class 2 HDACs so far. Here we present the structure of the bacterial FB188 HDAH (histone deacetylase-like amidohydrolase from Bordetella/ Alcaligenes strain FB188) that reveals high sequential and functional homology to human class 2 HDACs. FB188 HDAH is capable to remove the acetyl moiety from acetylated histones. Several HDAC-specific inhibitors, which have been shown to inhibit tumor activity in both pre-clinical models and in clinical trials, also inhibit FB188 HDAH. We have determined the crystal structure of FB188 HDAH at a resolution of 1.6 Å in complex with the reaction product acetate, as well as in complex with the inhibitors suberoylanilide hydroxamic acid (SAHA) and cyclopentyle-propionyle hydroxamic acid (CypX) at a resolution of 1.57 Å and 1.75 Å, respectively. FB188 HDAH exhibits the canonical fold of class 1 HDACs and contains a catalytic zinc ion. The highest structural diversity compared to class 1 enzymes is found in loop regions especially in the area around the entrance of the active site, indicating significant differences among the acetylated proteins binding to class 1 and 2 HDACs, respectively.