Abstract

NAD(P)-dependent steroid dehydrogenase-like (NSDHL), an essential enzyme in human cholesterol synthesis and a regulator of epidermal growth factor receptor (EGFR) trafficking pathways, has attracted interest as a therapeutic target due to its crucial relevance to cholesterol-related diseases and carcinomas. However, the development of pharmacological agents for targeting NSDHL has been hindered by the absence of the atomic details of NSDHL. In this study, we reported two X-ray crystal structures of human NSDHL, which revealed a detailed description of the coenzyme-binding site and the unique conformational change upon the binding of a coenzyme. A structure-based virtual screening and biochemical evaluation were performed and identified a novel inhibitor for NSDHL harboring suppressive activity towards EGFR. In EGFR-driven human cancer cells, treatment with the potent NSDHL inhibitor enhanced the antitumor effect of an EGFR kinase inhibitor. Overall, these findings could serve as good platforms for the development of therapeutic agents against NSDHL-related diseases.

中文翻译：

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人类NSDHL的晶体结构及其具有抑制EGFR活性潜力的新型抑制剂的开发

摘要

NAD（P）依赖性类固醇脱氢酶样（NSDHL）是人类胆固醇合成中必不可少的酶，也是表皮生长因子受体（EGFR）转运途径的调节剂，由于其与胆固醇-相关疾病和癌症。但是，由于缺乏NSDHL的原子细节，阻碍了靶向NSDHL的药理剂的开发。在这项研究中，我们报道了人类NSDHL的两种X射线晶体结构，揭示了辅酶结合位点的详细描述以及辅酶结合后的独特构象变化。进行了基于结构的虚拟筛选和生化评估，并鉴定了一种新型NSDHL抑制剂，该抑制剂对EGFR具有抑制活性。在EGFR驱动的人类癌细胞中，用有效的NSDHL抑制剂治疗可增强EGFR激酶抑制剂的抗肿瘤作用。总体而言，这些发现可以作为开发针对NSDHL相关疾病的治疗剂的良好平台。