skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

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 Lab. (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. Mon . "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 = {2017},
month = {4}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record

Citation Metrics:
Cited by: 19 works
Citation information provided by
Web of Science

Save / Share:

Works referencing / citing this record:

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


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


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


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


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


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