5JHS

Yeast 20S proteasome in complex with the peptidic epoxyketone inhibitor 15

5JHS の概要

• エントリーDOI: 10.2210/pdb5jhs/pdb
• 関連するPDBエントリー: 1G65 5CZ4
• 分子名称: Proteasome subunit alpha type-2, Proteasome subunit beta type-4, Proteasome subunit beta type-5, ... (19 entities in total)
• 機能のキーワード: hydrolase-hydrolase inhibitor complex, proteasome, inhibitor, binding analysis, hydrolase/hydrolase inhibitor
• 由来する生物種: Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast); 詳細
• 細胞内の位置: Cytoplasm: P23639 P22141 P30656 P23724 P30657 P38624 P23638 P40303 P32379 P40302 P21242 P21243 P25043 P25451
• タンパク質・核酸の鎖数: 28
• 化学式量合計: 734061.35

構造登録者

Huber, E.M.,Groll, M. (登録日: 2016-04-21, 公開日: 2016-08-03, 最終更新日: 2024-11-20)

主引用文献

Xin, B.T.,de Bruin, G.,Huber, E.M.,Besse, A.,Florea, B.I.,Filippov, D.V.,van der Marel, G.A.,Kisselev, A.F.,van der Stelt, M.,Driessen, C.,Groll, M.,Overkleeft, H.S.
Structure-Based Design of beta 5c Selective Inhibitors of Human Constitutive Proteasomes.
J.Med.Chem., 59:7177-7187, 2016

PubMed Abstract: This work reports the development of highly potent and selective inhibitors of the β5c 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 β1c/i, β2c/i, and β5i 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 β5c in cells expressing both constitutive proteasomes and immunoproteasomes.

PubMed: 27438186
DOI: 10.1021/acs.jmedchem.6b00705

実験手法

X-RAY DIFFRACTION (3 Å)