期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 62, 期 1, 页码 359-370出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.8b01025
关键词
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资金
- National Science Center [UMO-2014/15/B/NZ7/01014, UMO-2015/17/N/NZ1/01772, UMO-2016/23/N/ST5/02812]
- William and Ella Owens Medical Research Foundation
- San Antonio Nathan Shock Center of Excellence in the Biology of Aging Pilot Grants Program [NIH/P30]
- Voelcker Fund New Investigator Award
Proline- and arginine-rich peptide PR11 is an allosteric inhibitor of 20S proteasome. We modified its sequence inter alia by introducing HbYX, RYX, or RHbX C-terminal extensions (Hb, hydrophobic moiety; R, arginine; Y, tyrosine; X, any residue). Consequently, we were able to improve inhibitory potency or to convert inhibitors into strong activators: the former with an aromatic penultimate Hb residue and the latter with the HbYX motif. The PR peptide activator stimulated 20S proteasome in vitro to efficiently degrade protein substrates, such as alpha-synuclein and enolase, but also activated proteasome in cultured fibroblasts. The positive and negative PR modulators differently influenced the proteasome conformational dynamics and affected opening of the substrate entry pore. The resolved crystal structure showed PR inhibitor bound far from the active sites, at the proteasome outer face, in the pocket used by natural activators. Our studies indicate the opportunity to tune proteasome activity by allosteric regulators based on PR peptide scaffold.
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