6JKG

The NAD+-free form of human NSDHL

6JKG の概要

• エントリーDOI: 10.2210/pdb6jkg/pdb
• 分子名称: Sterol-4-alpha-carboxylate 3-dehydrogenase, decarboxylating (2 entities in total)
• 機能のキーワード: cholesterol, dehydrogenase, oxidoreductase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 54512.17

構造登録者

Kim, D.,Lee, S.J.,Lee, B. (登録日: 2019-02-28, 公開日: 2020-03-04, 最終更新日: 2023-11-22)

主引用文献

Kim, D.G.,Cho, S.,Lee, K.Y.,Cheon, S.H.,Yoon, H.J.,Lee, J.Y.,Kim, D.,Shin, K.S.,Koh, C.H.,Koo, J.S.,Choi, Y.,Lee, H.H.,Oh, Y.K.,Jeong, Y.S.,Chung, S.J.,Baek, M.,Jung, K.Y.,Lim, H.J.,Kim, H.S.,Park, S.J.,Lee, J.Y.,Lee, S.J.,Lee, B.J.
Crystal structures of human NSDHL and development of its novel inhibitor with the potential to suppress EGFR activity.
Cell.Mol.Life Sci., 78:207-225, 2021

PubMed 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.

PubMed: 32140747
DOI: 10.1007/s00018-020-03490-2

実験手法

X-RAY DIFFRACTION (2.9 Å)