期刊
ACS COMBINATORIAL SCIENCE
卷 20, 期 5, 页码 269-276出版社
AMER CHEMICAL SOC
DOI: 10.1021/acscombsci.7b00193
关键词
20S proteasome stimulators; peptide FRET reporter; gate-opening stimulators
资金
- Purdue University School of Pharmacy
- Purdue University Center for Cancer Research NIH [P30 CA023168]
- Ralph W. and Grace M. Showalter Research Trust
- NATIONAL CANCER INSTITUTE [P30CA023168] Funding Source: NIH RePORTER
To attenuate an overabundance of cellular protein, it has been hypothesized that the 20S core particle (20S CP) of the proteasome can be chemically stimulated to degrade proteins into nontoxic peptides more quickly. Screening for small molecule 20S CP stimulators is typically performed with a reporter peptide composed of four amino acids and a coumarin group that is released upon proteasome-mediated hydrolysis to generate a fluorescent signal. Screening with this small reporter can lead to false negatives because the reporter peptide is rapidly turned-over without stimulation. To improve the screening for 20S CP stimulators, we have developed a peptide FRET reporter nearly four times more sensitive to stimulation but still amenable for high throughput screening. Through application of our FRET reporter, we have discovered two 20S CP gate-opening stimulators and also a molecule that elicits its mechanism of action through an interaction with a 20S CP active site.
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