A DNA aptamer reveals an allosteric site for inhibition in metallo-β-lactamases
Abstract
The hydrolysis of β-lactam antibiotics by β-lactamase enzymes is the most prominent antibiotic resistance mechanism for many pathogenic bacteria. Out of this broad class of enzymes, metallo-β-lactamases are of special clinical interest because of their broad substrate specificities. Several in vitro inhibitors for various metallo-β-lactamases have been reported with no clinical efficacy. Previously, we described a 10-nucleotide single stranded DNA aptamer (10-mer) that inhibits Bacillus cereus 5/B/6 metallo-β-lactamase very effectively. Here, we find that the aptamer shows uncompetitive inhibition of Bacillus cereus 5/B/ 6 metallo-β-lactamase during cefuroxime hydrolysis. To understand the mechanism of inhibition, we report a 2.5 Å resolution X-ray crystal structure and solution-state NMR analysis of the free enzyme. Chemical shift perturbations were observed in the HSQC spectra for several residues upon titrating with increasing concentrations of the 10-mer. In the X-ray crystal structure, these residues are distal to the active site, suggesting an allosteric mechanism for the aptamer inhibition of the enzyme. HADDOCK molecular docking simulations suggest that the 10-mer docks 26 Å from the active site. We then mutated the three lysine residues in the basic binding patch to glutamine and measured the catalytic activity and inhibition by the 10-mer. No significant inhibition of these mutantsmore »
- Authors:
-
[1];
[1]
- Texas Tech Univ., Lubbock, TX (United States)
- Texas Tech Univ. Health Sciences Center, Lubbock, TX (United States)
- Publication Date:
- Research Org.:
- SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL); Stanford Univ., CA (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institute of General Medical Sciences (NIGMS); National Institutes of Health (NIH); National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); Welch Foundation
- OSTI Identifier:
- 1903990
- Grant/Contract Number:
- AC01-76SF00515; AC02-76SF00515; AC03-76SF00515; P41GM103393; R01AR063634; R35GM124979; D-1876
- Resource Type:
- Accepted Manuscript
- Journal Name:
- PLoS ONE
- Additional Journal Information:
- Journal Volume: 14; Journal Issue: 4; Journal ID: ISSN 1932-6203
- Publisher:
- Public Library of Science
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; crystal structure; enzyme inhibitors; hydrolysis; enzyme structure; Bacillus cereus; lysine; enzymes; antibiotics
Citation Formats
Khan, Nazmul H., Bui, Anthony A., Xiao, Yang, Sutton, R. Bryan, Shaw, Robert W., Wylie, Benjamin J., and Latham, Michael P. A DNA aptamer reveals an allosteric site for inhibition in metallo-β-lactamases. United States: N. p., 2019.
Web. doi:10.1371/journal.pone.0214440.
Khan, Nazmul H., Bui, Anthony A., Xiao, Yang, Sutton, R. Bryan, Shaw, Robert W., Wylie, Benjamin J., & Latham, Michael P. A DNA aptamer reveals an allosteric site for inhibition in metallo-β-lactamases. United States. https://doi.org/10.1371/journal.pone.0214440
Khan, Nazmul H., Bui, Anthony A., Xiao, Yang, Sutton, R. Bryan, Shaw, Robert W., Wylie, Benjamin J., and Latham, Michael P. Mon .
"A DNA aptamer reveals an allosteric site for inhibition in metallo-β-lactamases". United States. https://doi.org/10.1371/journal.pone.0214440. https://www.osti.gov/servlets/purl/1903990.
@article{osti_1903990,
title = {A DNA aptamer reveals an allosteric site for inhibition in metallo-β-lactamases},
author = {Khan, Nazmul H. and Bui, Anthony A. and Xiao, Yang and Sutton, R. Bryan and Shaw, Robert W. and Wylie, Benjamin J. and Latham, Michael P.},
abstractNote = {The hydrolysis of β-lactam antibiotics by β-lactamase enzymes is the most prominent antibiotic resistance mechanism for many pathogenic bacteria. Out of this broad class of enzymes, metallo-β-lactamases are of special clinical interest because of their broad substrate specificities. Several in vitro inhibitors for various metallo-β-lactamases have been reported with no clinical efficacy. Previously, we described a 10-nucleotide single stranded DNA aptamer (10-mer) that inhibits Bacillus cereus 5/B/6 metallo-β-lactamase very effectively. Here, we find that the aptamer shows uncompetitive inhibition of Bacillus cereus 5/B/ 6 metallo-β-lactamase during cefuroxime hydrolysis. To understand the mechanism of inhibition, we report a 2.5 Å resolution X-ray crystal structure and solution-state NMR analysis of the free enzyme. Chemical shift perturbations were observed in the HSQC spectra for several residues upon titrating with increasing concentrations of the 10-mer. In the X-ray crystal structure, these residues are distal to the active site, suggesting an allosteric mechanism for the aptamer inhibition of the enzyme. HADDOCK molecular docking simulations suggest that the 10-mer docks 26 Å from the active site. We then mutated the three lysine residues in the basic binding patch to glutamine and measured the catalytic activity and inhibition by the 10-mer. No significant inhibition of these mutants was observed by the 10-mer as compared to wild type. Interestingly, mutation of Lys50 (Lys78; according to standard MBL numbering system) resulted in reduced enzymatic activity relative to wild type in the absence of inhibitor, further highlighting an allosteric mechanism for inhibition.},
doi = {10.1371/journal.pone.0214440},
journal = {PLoS ONE},
number = 4,
volume = 14,
place = {United States},
year = {Mon Apr 22 00:00:00 EDT 2019},
month = {Mon Apr 22 00:00:00 EDT 2019}
}
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