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

Cellular and Molecular Life Sciences : CMLS
Dong-Gyun KimBong-Jin Lee

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.

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Citations

Aug 21, 2020·BMC Medical Genetics·D HettiarachchiV H W Dissanayake
May 20, 2021·Biochemical Pharmacology·Babita MadanDavid J Leaver

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Methods Mentioned

BETA
PCR
gel filtration
X-ray
light scattering
static light scattering
chip
fluorescence-activated cell sorting
electrophoresis
size-exclusion
thermal shift

Software Mentioned

Dali
Coot
Phaser
GraphPad Prism
Protein Preparation Wizard in Maestro
FlowJo
MR
refine
Schrödinger Suite
MicroCal Origin

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