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Assays for Validating Histone Acetyltransferase Inhibitors
Published on: August 6, 2020
Novel structural insights into class I and II histone deacetylases
1Department of Molecular Structural Biology, Institute for Microbiology and Genetics, GZMB, Georg-August-University Göttingen, 37077 Göttingen, Germany. rficner@uni-goettingen.de
Abstract:
The deacetylation of modified lysine residues of histones and other proteins is catalyzed by histone deacetlyases (HDACs). HDACs play an important role in the regulation of many biological processes such as cell-cycle, cell differentiation and survival. Since the inhibition of HDACs leads to growth arrest, differentiation or apoptosis of tumor cell lines, HDACs are promising targets for cancer therapy. Knowledge of the three-dimensional structures of HDACs with bound substrate or inhibitor molecules is a prerequisite for rational structure-based drug design. Here recent developments in the crystal structure analysis of human HDAC4, HDAC7, and HDAC8, which all belong to the family of zinc ion-dependent HDACs, are described. Crystallographic and biochemical studies of the catalytic domains of HDAC4 and HDAC7 revealed the molecular basis for their low enzymatic activity. Furthermore, the role of a second, structural zinc ion has been elucidated. The structures of HDAC8 with bound substrate-like peptide molecule demonstrate the functional role of a conserved aspartate residue located at the rim of the active site in substrate recognition. Structures of these three HDACs with various bound inhibitor molecules will provide the structural basis for further development of HDAC inhibitors with improved isoform-specific selectivity.
Insights
Histone deacetylases (HDACs) are key targets in cancer therapy. New crystal structures of HDAC4, HDAC7, and HDAC8 reveal insights into their function and inhibition, aiding in developing more selective cancer drugs.
Area of Science:
- Biochemistry
- Structural Biology
- Cancer Research
Background:
- Histone deacetylases (HDACs) catalyze protein deacetylation, regulating vital biological processes.
- HDAC inhibition induces tumor cell apoptosis, making HDACs promising cancer therapy targets.
- Structure-based drug design requires knowledge of HDAC three-dimensional structures with substrates or inhibitors.
Purpose of the Study:
- To describe recent developments in the crystal structure analysis of human HDAC4, HDAC7, and HDAC8.
- To elucidate the molecular basis for the low enzymatic activity of HDAC4 and HDAC7.
- To understand the role of a structural zinc ion and substrate recognition in HDAC8.
Main Methods:
- X-ray crystallography of human HDAC4, HDAC7, and HDAC8 catalytic domains.
- Biochemical studies to assess enzymatic activity.
- Analysis of HDAC structures with bound substrate-like peptides and inhibitor molecules.
Main Results:
- Crystallographic and biochemical studies revealed the molecular basis for low enzymatic activity in HDAC4 and HDAC7.
- The function of a second, structural zinc ion in HDACs was elucidated.
- HDAC8 structures with bound substrate-like peptides highlighted the role of a conserved aspartate in substrate recognition.
Conclusions:
- Structural insights into HDAC4, HDAC7, and HDAC8 are crucial for understanding their function.
- The elucidated structural features provide a basis for developing novel HDAC inhibitors.
- Further development of HDAC inhibitors with improved isoform-specific selectivity is supported by these structural findings.
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