Crystal structures of human NSDHL and development of its novel inhibitor with the potential to suppress EGFR activity.
3-Hydroxysteroid Dehydrogenases
/ antagonists & inhibitors
Binding Sites
Cell Line, Tumor
Cell Survival
/ drug effects
Cholesterol
/ chemistry
Crystallography, X-Ray
Enzyme Inhibitors
/ chemistry
ErbB Receptors
/ antagonists & inhibitors
Erlotinib Hydrochloride
/ chemistry
Humans
Kinetics
Molecular Docking Simulation
Mutagenesis, Site-Directed
NAD
/ chemistry
Protein Structure, Tertiary
Recombinant Proteins
/ biosynthesis
Signal Transduction
Cholesterol synthesis pathway
EGFR
Membrane-anchored protein
NSDHL
Structure-based drug design
Journal
Cellular and molecular life sciences : CMLS
ISSN: 1420-9071
Titre abrégé: Cell Mol Life Sci
Pays: Switzerland
ID NLM: 9705402
Informations de publication
Date de publication:
Jan 2021
Jan 2021
Historique:
received:
17
09
2019
accepted:
17
02
2020
revised:
29
01
2020
pubmed:
7
3
2020
medline:
17
2
2021
entrez:
7
3
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32140747
doi: 10.1007/s00018-020-03490-2
pii: 10.1007/s00018-020-03490-2
doi:
Substances chimiques
Enzyme Inhibitors
0
Recombinant Proteins
0
NAD
0U46U6E8UK
Cholesterol
97C5T2UQ7J
Erlotinib Hydrochloride
DA87705X9K
3-Hydroxysteroid Dehydrogenases
EC 1.1.-
Nsdhl protein, human
EC 1.1.1.170
EGFR protein, human
EC 2.7.10.1
ErbB Receptors
EC 2.7.10.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
207-225Subventions
Organisme : National Research Foundation of Korea
ID : NRF-2018R1A2A1A19018526
Organisme : National Research Foundation of Korea
ID : NRF-2018R1A5A2024425
Organisme : National Research Foundation of Korea
ID : NRF-2016R1C1B2014609
Organisme : National Research Foundation of Korea
ID : NRF-2018R1A6B4023605
Organisme : National Research Foundation of Korea
ID : NRF-2019R1H1A1102102
Organisme : National Research Foundation of Korea
ID : NRF-2017R1C1B2012225
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