Crystal structures of human NSDHL and development of its novel inhibitor with the potential to suppress EGFR activity

Dong Gyun Kim, Sujin Cho, Kyu Yeon Lee, Seung Ho Cheon, Hye Jin Yoon, Joo Youn Lee, Dongyoon Kim, Kwang Soo Shin, Choong Hyun Koh, Ji Sung Koo, Yuri Choi, Hyung Ho Lee, Yu Kyoung Oh, Yoo Seong Jeong, Suk Jae Chung, Moonkyu Baek, Kwan Young Jung, Hyo Jin Lim, Hyoun Sook Kim, Sung Jean ParkJeong Yeon Lee, Sang Jae Lee, Bong Jin Lee

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


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.

Original languageEnglish
Pages (from-to)207-225
Number of pages19
JournalCellular and Molecular Life Sciences
Issue number1
StatePublished - 2021 Jan


  • Cholesterol synthesis pathway
  • EGFR
  • Membrane-anchored protein
  • Structure-based drug design


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