7QUN

CryoEM structure of mammalian AAP in complex with Meropenem

7QUN の概要

• エントリーDOI: 10.2210/pdb7qun/pdb
• 関連するPDBエントリー: 7px8
• EMDBエントリー: 14149
• 分子名称: Acylamino-acid-releasing enzyme, (2S,3R,4S)-4-{[(3S,5S)-5-(dimethylcarbamoyl)pyrrolidin-3-yl]sulfanyl}-2-[(2S,3R)-3-hydroxy-1-oxobutan-2-yl]-3-methyl-3,4-dihydro-2H-pyrrole-5-carboxylic acid (2 entities in total)
• 機能のキーワード: inhibitor, complex, acylaminoacyl-peptidase, meropenem, carbapenem, acylpeptide hydrolase, hydrolase
• 由来する生物種: Sus scrofa domesticus (domestic pig)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 326839.48

構造登録者

Kiss-Szeman, A.J.,Harmat, V.,Straner, P.,Jakli, I.,Menyhard, K.D.,Masiulis, S.,Perczel, A. (登録日: 2022-01-18, 公開日: 2022-11-16, 最終更新日: 2025-07-09)

主引用文献

Kiss-Szeman, A.J.,Takacs, L.,Orgovan, Z.,Straner, P.,Jakli, I.,Schlosser, G.,Masiulis, S.,Harmat, V.,Menyhard, D.K.,Perczel, A.
A carbapenem antibiotic inhibiting a mammalian serine protease: structure of the acylaminoacyl peptidase-meropenem complex.
Chem Sci, 13:14264-14276, 2022

PubMed Abstract: The structure of porcine AAP (pAAP) in a covalently bound complex with meropenem was determined by cryo-EM to 2.1 Å resolution, showing the mammalian serine-protease inhibited by a carbapenem antibiotic. AAP is a modulator of the ubiquitin-proteasome degradation system and the site of a drug-drug interaction between the widely used antipsychotic, valproate and carbapenems. The active form of pAAP - a toroidal tetramer - binds four meropenem molecules covalently linked to the catalytic Ser587 of the serine-protease triad, in an acyl-enzyme state. AAP is hindered from fully processing the antibiotic by the displacement and protonation of His707 of the catalytic triad. We show that AAP is made susceptible to the association by its unusually sheltered active pockets and flexible catalytic triads, while the carbapenems possess sufficiently small substituents on their β-lactam rings to fit into the shallow substrate-specificity pocket of the enzyme.

PubMed: 36545146
DOI: 10.1039/d2sc05520a

実験手法

ELECTRON MICROSCOPY (2.1 Å)