The pivotal role of histidine 976 in human histone deacetylase 4 for enzyme function and ligand recognition

IF 4.5 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Bioorganic Chemistry Pub Date : 2024-10-10 DOI:10.1016/j.bioorg.2024.107883

{"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 HDAC4_wt 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_H976Y 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 HDAC4_wt. 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 HDAC4_H976A 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_wt.

查看原文

微信好友朋友圈 QQ好友复制链接

本刊更多论文

组氨酸 976 在人类组蛋白去乙酰化酶 4 中对酶功能和配体识别的关键作用

人类组蛋白去乙酰化酶 4（HDAC4）属于锌依赖性组蛋白去乙酰化酶 IIa 类。HDAC4 已成为各种适应症的靶点，尤其是亨廷顿氏病、心力衰竭和癌症。为了减少不必要的副作用，开发具有同工酶选择性的抑制剂是非常有利的，但由于 HDAC 家族的活性中心高度保守，开发同工酶选择性抑制剂是一项重大挑战。与此相反，HDAC4H976Y 中相应酪氨酸的侧链采用内构象，因此能够稳定脱乙酰化反应的中间状态并阻止进入脚袋。选择性 HDAC4 抑制剂与足部口袋的结合在 HDAC4 变体中会增强，这些变体主要具有小的疏水性侧链，但也有中等的疏水性或极性侧链。因此，我们建议将 HDAC4H976A 和其他 HDAC4 变体作为在筛选活动中发现和丰富 HDAC4 选择性脚袋结合剂的有前途的工具，而这些脚袋结合剂在使用 HDAC4wt 的传统筛选中可能会被忽视。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文去求助

来源期刊

Bioorganic Chemistry 生物-生化与分子生物学

CiteScore

9.70

自引率

3.90%

发文量

679

审稿时长

31 days

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.