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Title: Molecular Basis of Substrate Recognition and Product Release by the Klebsiella pneumoniae Carbapenemase (KPC-2)

Abstract

Carbapenem-resistant Enterobacteriaceae are resistant to most β-lactam antibiotics due to the production of the Klebsiella pneumoniae carbapenemase (KPC-2) class A β-lactamase. Here, we present the first product complex crystal structures of KPC-2 with β-lactam antibiotics containing hydrolyzed cefotaxime and faropenem. They provide experimental insights into substrate recognition by KPC-2 and its unique cephalosporinase/carbapenemase activity. These structures also represent the first product complexes for a wild-type serine β-lactamase, elucidating the product release mechanism of these enzymes in general.

Authors:
 [1];  [1]; ORCiD logo [1]
  1. Univ. of South Florida, Tampa, FL (United States)
Publication Date:
Research Org.:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Org.:
National Institutes of Health (NIH)
OSTI Identifier:
1368248
Grant/Contract Number:  
AI103158
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Journal of Medicinal Chemistry
Additional Journal Information:
Journal Volume: 60; Journal Issue: 8; Journal ID: ISSN 0022-2623
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; Antimicrobial agents; Peptides and proteins; Monomers; Chemical structure; Conformation

Citation Formats

Pemberton, Orville A., Zhang, Xiujun, and Chen, Yu. Molecular Basis of Substrate Recognition and Product Release by the Klebsiella pneumoniae Carbapenemase (KPC-2). United States: N. p., 2017. Web. doi:10.1021/acs.jmedchem.7b00158.
Pemberton, Orville A., Zhang, Xiujun, & Chen, Yu. Molecular Basis of Substrate Recognition and Product Release by the Klebsiella pneumoniae Carbapenemase (KPC-2). United States. https://doi.org/10.1021/acs.jmedchem.7b00158
Pemberton, Orville A., Zhang, Xiujun, and Chen, Yu. 2017. "Molecular Basis of Substrate Recognition and Product Release by the Klebsiella pneumoniae Carbapenemase (KPC-2)". United States. https://doi.org/10.1021/acs.jmedchem.7b00158. https://www.osti.gov/servlets/purl/1368248.
@article{osti_1368248,
title = {Molecular Basis of Substrate Recognition and Product Release by the Klebsiella pneumoniae Carbapenemase (KPC-2)},
author = {Pemberton, Orville A. and Zhang, Xiujun and Chen, Yu},
abstractNote = {Carbapenem-resistant Enterobacteriaceae are resistant to most β-lactam antibiotics due to the production of the Klebsiella pneumoniae carbapenemase (KPC-2) class A β-lactamase. Here, we present the first product complex crystal structures of KPC-2 with β-lactam antibiotics containing hydrolyzed cefotaxime and faropenem. They provide experimental insights into substrate recognition by KPC-2 and its unique cephalosporinase/carbapenemase activity. These structures also represent the first product complexes for a wild-type serine β-lactamase, elucidating the product release mechanism of these enzymes in general.},
doi = {10.1021/acs.jmedchem.7b00158},
url = {https://www.osti.gov/biblio/1368248}, journal = {Journal of Medicinal Chemistry},
issn = {0022-2623},
number = 8,
volume = 60,
place = {United States},
year = {Mon Apr 17 00:00:00 EDT 2017},
month = {Mon Apr 17 00:00:00 EDT 2017}
}

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Cited by: 38 works
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Works referenced in this record:

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Works referencing / citing this record:

Molecular Basis of Class A β-Lactamase Inhibition by Relebactam
journal, August 2019


Molecular Basis of Class A β-Lactamase Inhibition by Relebactam
journal, August 2019


Antibacterial Spectrum of a Tetrazole-Based Reversible Inhibitor of Serine β-Lactamases
journal, May 2018


Cyclic boronates as versatile scaffolds for KPC-2 β-lactamase inhibition
journal, January 2020


Phenylboronic Acids Probing Molecular Recognition against Class A and Class C β-lactamases
journal, September 2019


β-Lactamases and β-Lactamase Inhibitors in the 21st Century
journal, August 2019


Discovery of dual-activity small-molecule ligands of Pseudomonas aeruginosa LpxA and LpxD using SPR and X-ray crystallography
journal, October 2019


Mechanistic Insights into β-Lactamase-Catalysed Carbapenem Degradation Through Product Characterisation
journal, September 2019


Phenylboronic Acids Probing Molecular Recognition against Class A and Class C β-lactamases
journal, September 2019


Influence of substrates and inhibitors on the structure of Klebsiella pneumoniae carbapenemase-2
journal, June 2019


In silico identification and experimental validation of hits active against KPC-2 β-lactamase
journal, November 2018


Unravelling ceftazidime/avibactam resistance of KPC-28, a KPC-2 variant lacking carbapenemase activity
journal, May 2019