2GPL

TMC-95 based biphenyl-ether macrocycles: specific proteasome inhibitors

2GPL の概要

• エントリーDOI: 10.2210/pdb2gpl/pdb
• 関連するPDBエントリー: 1JD2 1RYP
• 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: proteasomal subunit fold represents an antiparallel beta-sheet flanked by helices; ntn-hydrolase, hydrolase
• 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: 705527.59

構造登録者

Groll, M.,Goetz, M.,Kaiser, M.,Weyher, E.,Moroder, M. (登録日: 2006-04-18, 公開日: 2006-07-11, 最終更新日: 2023-08-30)

主引用文献

Groll, M.,Goetz, M.,Kaiser, M.,Weyher, E.,Moroder, L.
TMC-95-Based Inhibitor Design Provides Evidence for the Catalytic Versatility of the Proteasome.
Chem.Biol., 13:607-614, 2006

PubMed Abstract: TMC-95's natural cyclic tripeptide metabolites represent potent competitive proteasome inhibitors. The constrained conformation of TMC-95 proteasomal inhibitors provides the driving force for entropically high-affinity binding. Based on the crystal structure of the proteasome:TMC-95A complex, the synthetically challenging TMC-95 core structure was used for the design and synthesis of less demanding biphenyl-ether macrocycles, in which the biphenyl-ether moiety functions as an endocyclic clamp restricting its tripeptide backbone. These simplified analogs allowed us to identify high plasticity of the proteasomal tryptic-like specificity pocket. Biphenyl-ether compounds extended with an amide group were hydrolyzed by the proteasome, although the crystal structure of such proteasome:biphenyl-ether complexes revealed quenching of proteolysis at the acyl-enzyme intermediate. Our data reveal that biphenyl-ether derivatives bind noncovalently to the proteasomal tryptic-like active site in a reversible substrate-like manner without allosteric changes of active site residues.

PubMed: 16793518
DOI: 10.1016/j.chembiol.2006.04.005

実験手法

X-RAY DIFFRACTION (2.81 Å)