4HRC

Crystal structure of yeast 20S proteasome in complex with epoxyketone carmaphycin analogue 3

4HRC の概要

• エントリーDOI: 10.2210/pdb4hrc/pdb
• 関連するPDBエントリー: 4HND 4HNP
• 関連するBIRD辞書のPRD_ID: PRD_000930
• 分子名称: Proteasome component Y7, Proteasome component C11, Proteasome component PRE2, ... (16 entities in total)
• 機能のキーワード: proteasome, inhibitor, carmaphycin, epoxyketone, vinylketone, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Saccharomyces cerevisiae (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: 707116.20

構造登録者

Trivella, D.B.B.,Stein, M.,Groll, M. (登録日: 2012-10-27, 公開日: 2014-01-29, 最終更新日: 2024-11-20)

主引用文献

Trivella, D.B.,Pereira, A.R.,Stein, M.L.,Kasai, Y.,Byrum, T.,Valeriote, F.A.,Tantillo, D.J.,Groll, M.,Gerwick, W.H.,Moore, B.S.
Enzyme inhibition by hydroamination: design and mechanism of a hybrid carmaphycin-syringolin enone proteasome inhibitor.
Chem.Biol., 21:782-791, 2014

PubMed Abstract: Hydroamination reactions involving the addition of an amine to an inactivated alkene are entropically prohibited and require strong chemical catalysts. While this synthetic process is efficient at generating substituted amines, there is no equivalent in small molecule-mediated enzyme inhibition. We report an unusual mechanism of proteasome inhibition that involves a hydroamination reaction of alkene derivatives of the epoxyketone natural product carmaphycin. We show that the carmaphycin enone first forms a hemiketal intermediate with the catalytic Thr1 residue of the proteasome before cyclization by an unanticipated intramolecular alkene hydroamination reaction, resulting in a stable six-membered morpholine ring. The carmaphycin enone electrophile, which does not undergo a 1,4-Michael addition as previously observed with vinyl sulfone and α,β-unsaturated amide-based inhibitors, is partially reversible and gives insight into the design of proteasome inhibitors for cancer chemotherapy.

PubMed: 24930969
DOI: 10.1016/j.chembiol.2014.04.010

実験手法

X-RAY DIFFRACTION (2.8 Å)