{"title":"The pivotal role of histidine 976 in human histone deacetylase 4 for enzyme function and ligand recognition","authors":"","doi":"10.1016/j.bioorg.2024.107883","DOIUrl":null,"url":null,"abstract":"<div><div>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.</div><div>According to current knowledge it is assumed that H976 in HDAC4<sub>wt</sub> 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 HDAC4<sub>H976Y</sub> adopts the in-conformation, and is thus able to stabilize the intermediate state of the deacetylation reaction and block access to the foot pocket.</div><div>In this study, we provide evidence that a dynamic equilibrium exists between the in- and out-conformation in HDAC4<sub>wt</sub>. 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.</div><div>Therefore, we propose HDAC4<sub>H976A</sub> 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 HDAC4<sub>wt</sub>.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":null,"pages":null},"PeriodicalIF":4.5000,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bioorganic Chemistry","FirstCategoryId":"92","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0045206824007880","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
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.
期刊介绍:
Bioorganic Chemistry publishes research that addresses biological questions at the molecular level, using organic chemistry and principles of physical organic chemistry. The scope of the journal covers a range of topics at the organic chemistry-biology interface, including: enzyme catalysis, biotransformation and enzyme inhibition; nucleic acids chemistry; medicinal chemistry; natural product chemistry, natural product synthesis and natural product biosynthesis; antimicrobial agents; lipid and peptide chemistry; biophysical chemistry; biological probes; bio-orthogonal chemistry and biomimetic chemistry.
For manuscripts dealing with synthetic bioactive compounds, the Journal requires that the molecular target of the compounds described must be known, and must be demonstrated experimentally in the manuscript. For studies involving natural products, if the molecular target is unknown, some data beyond simple cell-based toxicity studies to provide insight into the mechanism of action is required. Studies supported by molecular docking are welcome, but must be supported by experimental data. The Journal does not consider manuscripts that are purely theoretical or computational in nature.
The Journal publishes regular articles, short communications and reviews. Reviews are normally invited by Editors or Editorial Board members. Authors of unsolicited reviews should first contact an Editor or Editorial Board member to determine whether the proposed article is within the scope of the Journal.