Structural characterization of fungus-specific histone deacetylase Hos3 provides insights into developing selective inhibitors with antifungal activity.
Structural characterization of fungus-specific histone deacetylase Hos3 provides insights into developing selective inhibitors with antifungal activity.
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真菌特异性组蛋白脱乙酰酶 Hos3 的结构表征为开发具有抗真菌活性的选择性抑制剂提供了见解
DOI：
10.1016/j.jbc.2022.102068
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发表时间：
2022-07
影响因子：
4.8
通讯作者：
Yang, Na
中科院分区：
文献类型：
--
作者：
Pang, Ningning;Sun, Jixue;Che, Shiyou;Yang, Na
真菌感染长期以来一直是人类的慢性甚至危及生命的问题。随着真菌感染的不断增加，对新型抗真菌药物的需求急剧增加，但由于高毒性或耐药性的发展，近15年来没有一类新的药物获得批准。因此，验证新的药物靶点，特别是真菌特异性靶点，可能有助于未来的药物设计。在这里，我们报道了酵母Hos3 （ScHos3）的晶体结构，这是一种真菌特异性组蛋白去乙酰化酶（HDAC），在真菌的生命周期中起着重要作用。由于乙酰化修饰在真菌感染的许多方面都很重要，Hos3的物种特异性使其成为开发新型抗真菌药物的理想靶点。在这项研究中，我们发现ScHos3在溶液中形成了一个功能性的同二聚体，并且鉴定了对其去乙酰化活性至关重要的二聚体关键残基。我们通过分子动力学模拟和与哺乳动物hHDAC6的结构比较来确定ScHos3催化核的独特特征。此外，通过基于结构的虚拟筛选和体外酶分析，鉴定了一种对ScHos3有偏好的小分子抑制剂。本文报道的ScHos3的结构信息和调控干扰为设计高效低毒的靶向真菌HDAC的选择性抑制剂或有可能克服与其他药物联合治疗中普遍存在的耐药问题提供了新的见解。
Fungal infection has long been a chronic and even life-threatening problem for humans. The demand for new antifungal drugs has increased dramatically as fungal infections have continued to increase, yet no new classes of drugs have been approved for nearly 15 years due to either high toxicity or development of drug resistance. Thus, validating new drug targets, especially fungus-specific targets, may facilitate future drug design. Here, we report the crystal structure of yeast Hos3 (ScHos3), a fungus-specific histone deacetylase (HDAC) that plays an important role in the life span of fungi. As acetylation modifications are important to many aspects of fungal infection, the species specificity of Hos3 makes it an ideal target for the development of new antifungal drugs. In this study, we show that ScHos3 forms a functional homodimer in solution, and key residues for dimerization crucial for its deacetylation activity were identified. We used molecular dynamics simulation and structural comparison with mammalian hHDAC6 to determine unique features of the ScHos3 catalytic core. In addition, a small-molecule inhibitor with a preference for ScHos3 was identified through structure-based virtual screening and in vitro enzymatic assays. The structural information and regulatory interferences of ScHos3 reported here provide new insights for the design of selective inhibitors that target fungal HDAC with high efficiency and low toxicity or that have the potential to overcome the prevailing problem of drug resistance in combination therapy with other drugs.
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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
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DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
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通讯作者：
Zwart PH