7QUN
CryoEM structure of mammalian AAP in complex with Meropenem
Summary for 7QUN
| Entry DOI | 10.2210/pdb7qun/pdb |
| Related | 7px8 |
| EMDB information | 14149 |
| Descriptor | 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) |
| Functional Keywords | inhibitor, complex, acylaminoacyl-peptidase, meropenem, carbapenem, acylpeptide hydrolase, hydrolase |
| Biological source | Sus scrofa domesticus (domestic pig) |
| Total number of polymer chains | 4 |
| Total formula weight | 326839.48 |
| Authors | Kiss-Szeman, A.J.,Harmat, V.,Straner, P.,Jakli, I.,Menyhard, K.D.,Masiulis, S.,Perczel, A. (deposition date: 2022-01-18, release date: 2022-11-16, Last modification date: 2024-10-16) |
| Primary citation | 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 Cited by 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: 36545146DOI: 10.1039/d2sc05520a PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.1 Å) |
Structure validation
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