Gossypol inhibits cullin neddylation by targeting SAG-CUL5 and RBX1-CUL1 complexes

Neoplasia : an International Journal for Oncology Research
Qing YuYi Sun

Abstract

Cullin-RING E3 ligase (CRL) is the largest family of E3 ubiquitin ligase, responsible for ubiquitylation of ∼20% of cellular proteins. CRL plays an important role in many biological processes, particularly in cancers due to abnormal activation. CRL activation requires neddylation, an enzymatic cascade transferring small ubiquitin-like protein NEDD8 to a conserved lysine residue on cullin proteins. Recent studies have validated that neddylation is an attractive anticancer target. In this study, we report the establishment of an Alpha-Screen-based high throughput screen (HTS) assay for in vitro CUL5 neddylation, and screened a library of 17,000 compounds including FDA approved drugs, natural products and synthetic drug-like small-molecule compounds. Gossypol, a natural compound derived from cotton seed, was identified as an inhibitor of cullin neddylation. Biochemical studies showed that gossypol blocked neddylation of both CUL5 and CUL1 through direct binding to SAG-CUL5 or RBX1-CUL1 complex, and CUL5-H572 plays a key role for gossypol binding. On cellular level, gossypol inhibited cullin neddylation in a variety of cancer cell lines and selectively caused accumulation of NOXA and MCL1, the substrates of CUL5 and CUL1, respectiv...Continue Reading

Citations

May 8, 2020·International Journal of Molecular Sciences·Karel Vališ, Petr Novák
Nov 25, 2020·Bioorganic & Medicinal Chemistry·Shu-Yu WangSai-Yang Zhang
Feb 13, 2021·Trends in Cell Biology·Guang LuHan-Ming Shen

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Methods Mentioned

BETA
neddylation
gel-filtration
electrophoresis
AlphaScreen
thermal
PCR
thermal shift
reverse-transcription PCR
Transfection
isothermal titration calorimetry

Software Mentioned

ImageJ
AlphaSignal
ImagJ
TargetMol
CompuSyn
SiteMap
LigPrep
GraphPad Prism
AlphaScreen
Schrödinger

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