Issue 48, 2022

A carbapenem antibiotic inhibiting a mammalian serine protease: structure of the acylaminoacyl peptidase–meropenem complex

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.

Graphical abstract: A carbapenem antibiotic inhibiting a mammalian serine protease: structure of the acylaminoacyl peptidase–meropenem complex

Supplementary files

Article information

Article type
Edge Article
Submitted
05 Okt. 2022
Accepted
06 Nov. 2022
First published
08 Nov. 2022
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2022,13, 14264-14276

A carbapenem antibiotic inhibiting a mammalian serine protease: structure of the acylaminoacyl peptidase–meropenem complex

A. J. Kiss-Szemán, L. Takács, Z. Orgován, P. Stráner, I. Jákli, G. Schlosser, S. Masiulis, V. Harmat, D. K. Menyhárd and A. Perczel, Chem. Sci., 2022, 13, 14264 DOI: 10.1039/D2SC05520A

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