5jhs
Yeast 20S proteasome in complex with the peptidic epoxyketone inhibitor 15
Structural highlights
FunctionPSA2_YEAST The proteasome degrades poly-ubiquitinated proteins in the cytoplasm and in the nucleus. It is essential for the regulated turnover of proteins and for the removal of misfolded proteins. The proteasome is a multicatalytic proteinase complex that is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. It has an ATP-dependent proteolytic activity. Publication Abstract from PubMedThis work reports the development of highly potent and selective inhibitors of the beta5c catalytic activity of human constitutive proteasomes. The work describes the design principles, large hydrophobic P3 residue and small hydrophobic P1 residue, that led to the synthesis of a panel of peptide epoxyketones; their evaluation and the selection of the most promising compounds for further analyses. Structure-activity relationships detail how in a logical order the beta1c/i, beta2c/i, and beta5i activities became resistant to inhibition as compounds were diversified stepwise. The most effective compounds were obtained as a mixture of cis- and trans-biscyclohexyl isomers, and enantioselective synthesis resolved this issue. Studies on yeast proteasome structures complexed with some of the compounds provide a rationale for the potency and specificity. Substitution of the N-terminus in the most potent compound for a more soluble equivalent led to a cell-permeable molecule that selectively and efficiently blocks beta5c in cells expressing both constitutive proteasomes and immunoproteasomes. Structure-Based Design of beta5c Selective Inhibitors of Human Constitutive Proteasomes.,Xin BT, de Bruin G, Huber EM, Besse A, Florea BI, Filippov DV, van der Marel GA, Kisselev AF, van der Stelt M, Driessen C, Groll M, Overkleeft HS J Med Chem. 2016 Aug 1. PMID:27438186[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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