The pivotal role of histidine 976 in human histone deacetylase 4 for enzyme function and ligand recognition Article Swipe
Markus Schweipert
,
Thomas Nehls
,
Eva Wurster
,
Jaqueline Böltner
,
Kuzmin Anton
,
Patrick Lammer
,
Frederik Lermyte
,
Franz‐Josef Meyer‐Almes
·
YOU?
·
· 2024
· Open Access
·
· DOI: https://doi.org/10.1016/j.bioorg.2024.107883
YOU?
·
· 2024
· Open Access
·
· DOI: https://doi.org/10.1016/j.bioorg.2024.107883
Human histone deacetylase 4 (HDAC4) belongs to class IIa of the zinc-dependent histone deacetylases. HDAC4 is an established target for various indication areas, in particular Huntington's disease, heart failure and cancer. To reduce unwanted side effects, it is advantageous to develop isozyme-selective inhibitors, which poses a major challenge due to the highly conserved active centers of the HDAC family. According to current knowledge it is assumed that H976 in HDAC4wt occurs exclusively in the out-conformation and thus the selective foot pocket is constitutively open. In contrast, the side chain of the corresponding tyrosine in HDAC4H976Y adopts the in-conformation, and is thus able to stabilize the intermediate state of the deacetylation reaction and block access to the foot pocket. In this study, we provide evidence that a dynamic equilibrium exists between the in- and out-conformation in HDAC4wt. The binding of selective HDAC4 inhibitors that address the foot pocket can be enhanced in HDAC4 variants with mainly small, but also medium hydrophobic or polar side chains. We attribute this to the fact that these side chains are preferentially present in the out-conformation. Therefore, we propose HDAC4H976A and other HDAC4 variants as promising tools to find and enrich HDAC4-selective foot pocket binders in screening campaigns that might have been overlooked in conventional screens with HDAC4wt.
Related Topics
Concepts
Chemistry
Histone deacetylase
Histidine
Enzyme
Biochemistry
Ligand (biochemistry)
Function (biology)
Histone
Histone deacetylase 2
Cell biology
DNA
Receptor
Biology
Metadata
- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.1016/j.bioorg.2024.107883
- OA Status
- hybrid
- Cited By
- 3
- References
- 37
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4403282923
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
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https://openalex.org/W4403282923Canonical identifier for this work in OpenAlex
- DOI
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https://doi.org/10.1016/j.bioorg.2024.107883Digital Object Identifier
- Title
-
The pivotal role of histidine 976 in human histone deacetylase 4 for enzyme function and ligand recognitionWork title
- Type
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articleOpenAlex work type
- Language
-
enPrimary language
- Publication year
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2024Year of publication
- Publication date
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2024-10-10Full publication date if available
- Authors
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Markus Schweipert, Thomas Nehls, Eva Wurster, Jaqueline Böltner, Kuzmin Anton, Patrick Lammer, Frederik Lermyte, Franz‐Josef Meyer‐AlmesList of authors in order
- Landing page
-
https://doi.org/10.1016/j.bioorg.2024.107883Publisher landing page
- Open access
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YesWhether a free full text is available
- OA status
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hybridOpen access status per OpenAlex
- OA URL
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https://doi.org/10.1016/j.bioorg.2024.107883Direct OA link when available
- Concepts
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Chemistry, Histone deacetylase, Histidine, Enzyme, Biochemistry, Ligand (biochemistry), Function (biology), Histone, Histone deacetylase 2, Cell biology, DNA, Receptor, BiologyTop concepts (fields/topics) attached by OpenAlex
- Cited by
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3Total citation count in OpenAlex
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2025: 3Per-year citation counts (last 5 years)
- References (count)
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37Number of works referenced by this work
- Related works (count)
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10Other works algorithmically related by OpenAlex
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