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Influence of the Active Site Flexibility on the Efficiency of Substrate Activation in the Active Sites of Bi-Zinc Metallo-β-Lactamases
The influence of the active site flexibility on the efficiency of catalytic reaction is studied by taking two members of metallo-β-lactamases, L1 and NDM-1, with the same substrate, imipenem. Active sites of these proteins are covered by L10 loops, and differences in their amino acid compositions af...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9610450/ https://www.ncbi.nlm.nih.gov/pubmed/36296624 http://dx.doi.org/10.3390/molecules27207031 |
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author | Krivitskaya, Alexandra V. Khrenova, Maria G. |
author_facet | Krivitskaya, Alexandra V. Khrenova, Maria G. |
author_sort | Krivitskaya, Alexandra V. |
collection | PubMed |
description | The influence of the active site flexibility on the efficiency of catalytic reaction is studied by taking two members of metallo-β-lactamases, L1 and NDM-1, with the same substrate, imipenem. Active sites of these proteins are covered by L10 loops, and differences in their amino acid compositions affect their rigidity. A more flexible loop in the NDM-1 brings additional flexibility to the active site in the ES complex. This is pronounced in wider distributions of key interatomic distances, such as the distance of the nucleophilic attack, coordination bond lengths, and covalent bond lengths in the substrate. Substrate activation, quantified by Fukui electrophilicity index of the carbonyl carbon atom of the substrate, is also sensitive to the active site flexibility. In the tighter and more rigid L1 enzyme-substrate complex, the substrate is activated more efficiently. In the NDM-1 containing system, only one third of the states are activated to the same extent. Other fractions demonstrate lower substrate activation. Efficiency of the substrate activation and rigidity of the ES complex influence the following chemical reaction. In the more rigid L1-containing system, the reaction barrier of the first step of the reaction is lower, and the first intermediate is more stabilized compared to the NDM-1 containing system. |
format | Online Article Text |
id | pubmed-9610450 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-96104502022-10-28 Influence of the Active Site Flexibility on the Efficiency of Substrate Activation in the Active Sites of Bi-Zinc Metallo-β-Lactamases Krivitskaya, Alexandra V. Khrenova, Maria G. Molecules Article The influence of the active site flexibility on the efficiency of catalytic reaction is studied by taking two members of metallo-β-lactamases, L1 and NDM-1, with the same substrate, imipenem. Active sites of these proteins are covered by L10 loops, and differences in their amino acid compositions affect their rigidity. A more flexible loop in the NDM-1 brings additional flexibility to the active site in the ES complex. This is pronounced in wider distributions of key interatomic distances, such as the distance of the nucleophilic attack, coordination bond lengths, and covalent bond lengths in the substrate. Substrate activation, quantified by Fukui electrophilicity index of the carbonyl carbon atom of the substrate, is also sensitive to the active site flexibility. In the tighter and more rigid L1 enzyme-substrate complex, the substrate is activated more efficiently. In the NDM-1 containing system, only one third of the states are activated to the same extent. Other fractions demonstrate lower substrate activation. Efficiency of the substrate activation and rigidity of the ES complex influence the following chemical reaction. In the more rigid L1-containing system, the reaction barrier of the first step of the reaction is lower, and the first intermediate is more stabilized compared to the NDM-1 containing system. MDPI 2022-10-18 /pmc/articles/PMC9610450/ /pubmed/36296624 http://dx.doi.org/10.3390/molecules27207031 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Krivitskaya, Alexandra V. Khrenova, Maria G. Influence of the Active Site Flexibility on the Efficiency of Substrate Activation in the Active Sites of Bi-Zinc Metallo-β-Lactamases |
title | Influence of the Active Site Flexibility on the Efficiency of Substrate Activation in the Active Sites of Bi-Zinc Metallo-β-Lactamases |
title_full | Influence of the Active Site Flexibility on the Efficiency of Substrate Activation in the Active Sites of Bi-Zinc Metallo-β-Lactamases |
title_fullStr | Influence of the Active Site Flexibility on the Efficiency of Substrate Activation in the Active Sites of Bi-Zinc Metallo-β-Lactamases |
title_full_unstemmed | Influence of the Active Site Flexibility on the Efficiency of Substrate Activation in the Active Sites of Bi-Zinc Metallo-β-Lactamases |
title_short | Influence of the Active Site Flexibility on the Efficiency of Substrate Activation in the Active Sites of Bi-Zinc Metallo-β-Lactamases |
title_sort | influence of the active site flexibility on the efficiency of substrate activation in the active sites of bi-zinc metallo-β-lactamases |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9610450/ https://www.ncbi.nlm.nih.gov/pubmed/36296624 http://dx.doi.org/10.3390/molecules27207031 |
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