The Structure of the Histone Deacetylase Family and the Use of Combined Computational Techniques

Axenic Jelio^*
*Correspondence: Axenic Jelio, Department of Biological Chemistry, National and Kapodistrian University of Athens, 11527 Athens, Greece, Email:

Keywords

Histone deacetylases • Catalytic domain • Deacetylases

Introduction

Histone Deacetylases (HDACs) are a group of enzymes that play a pivotal role in the regulation of gene expression by catalyzing the removal of acetyl groups from histone proteins, resulting in chromatin compaction and transcriptional repression. HDACs are involved in various cellular processes, including cell cycle regulation, differentiation, and apoptosis. Given their critical functions, HDACs have emerged as significant targets for therapeutic intervention in cancer, neurodegenerative diseases, and other conditions. This review provides an overview of the structural organization of the HDAC family and explores the use of combined computational techniques in understanding their function and aiding drug discovery efforts [1].

Literature Review

The HDAC family is divided into four main classes based on sequence homology and functional domains:

Class I HDACs: This class includes HDAC1, HDAC2, HDAC3, and HDAC8. These enzymes are primarily nuclear and are characterized by their catalytic domain, which is highly conserved. Class I HDACs are involved in the regulation of transcription and are ubiquitously expressed in various tissues.

Class II HDACs: This class is further divided into Class IIa (HDAC4, HDAC5, HDAC7 and HDAC9) and Class IIb (HDAC6 and HDAC10). Class IIa HDACs have a modular structure with a catalytic domain and regulatory domains that facilitate interaction with other proteins. They shuttle between the nucleus and cytoplasm, playing roles in signal transduction and development. Class IIb HDACs have unique structural features, such as two catalytic domains in HDAC6.

Class III HDACs (Sirtuins): Sirtuins (SIRT1-SIRT7) are NAD+-dependent deacetylases that differ significantly from other HDACs in their structure and catalytic mechanism. They are involved in various metabolic and stress response pathways and have been implicated in aging and longevity. Class IV HDACs: This class consists of a single member, HDAC11, which shares structural features with both Class I and Class II HDACs. HDAC11 is less well characterized but is believed to play roles in immune regulation and metabolism [2,3].

The catalytic domain of HDACs typically comprises a conserved arginase/deacetylase fold with a zinc ion at the active site, essential for catalytic activity. The structure includes a pair of catalytic residues (histidine and tyrosine or aspartate) that coordinate the zinc ion and facilitate the deacetylation reaction. In Class IIa HDACs, the catalytic efficiency is lower due to a substitution of the tyrosine residue, which affects zinc coordination. Class III HDACs (sirtuins) have a Rossmann fold domain that binds NAD+ and facilitates a unique deacetylation mechanism involving ADP-ribosylation. Molecular modeling and docking studies have been extensively used to investigate HDAC structures and their interactions with inhibitors. Homology modeling, based on the known structures of HDAC homologs, allows the construction of 3D models for HDACs whose crystal structures are not available. These models are crucial for understanding the binding sites and conformational flexibility of HDACs. Docking studies involve predicting the preferred orientation of a ligand (such as an HDAC inhibitor) when bound to an HDAC enzyme, providing insights into binding affinities and specific interactions. These studies help identify key residues involved in ligand binding and are instrumental in the rational design of potent HDAC inhibitors [4].

Discussion

MD simulations provide dynamic insights into the behavior of HDAC enzymes and their complexes with inhibitors over time. By simulating the atomic movements and interactions, MD simulations can reveal conformational changes, stability, and flexibility of HDACs in different states. This information is valuable for understanding the mechanisms of enzyme action and inhibitor binding. MD simulations have been used to study the conformational dynamics of HDACs, revealing the flexibility of active sites and the impact of mutations or post-translational modifications on HDAC function. These simulations also aid in refining docking results by considering the dynamic nature of protein-ligand interactions [5].

HDAC8, a member of Class I HDACs, has been extensively studied using computational techniques. Homology modelling and docking studies have identified critical residues involved in inhibitor binding. MD simulations have provided insights into the conformational flexibility of the enzyme and the dynamic behaviour of the inhibitor-enzyme complex. These studies have contributed to the design of selective HDAC8 inhibitors with potential therapeutic applications in cancer treatment. SIRT1, a well-studied sirtuin, has been the focus of numerous computational studies to understand its NAD⁺ dependent deacetylation mechanism. Molecular modeling has helped elucidate the binding mode of NAD⁺ and acetylated substrates. Docking studies have identified potential small-molecule modulators of SIRT1 activity. MD simulations have revealed the dynamic interactions between SIRT1, NAD⁺ and substrates, providing insights into the enzyme's regulatory mechanisms [6].

Conclusion

The structural diversity and functional significance of the HDAC family make them crucial targets for therapeutic intervention. Combined computational techniques, including molecular modeling, docking studies, and MD simulations, have significantly advanced our understanding of HDAC structure and function. These approaches have not only elucidated the molecular mechanisms of HDAC activity but also facilitated the rational design of selective inhibitors. Continued integration of computational techniques with experimental data will enhance our ability to develop effective HDAC-targeted therapies for various diseases.

Acknowledgement

None.

Conflict of Interest

None.

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