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High adaptability of the omega loop underlies the substrate-spectrum-extension evolution of a class A β-lactamase, PenL
The omega loop in β-lactamases plays a pivotal role in substrate recognition and catalysis, and some mutations in this loop affect the adaptability of the enzymes to new antibiotics. Various mutations, including substitutions, deletions, and intragenic duplications resulting in tandem repeats (TRs),...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5101513/ https://www.ncbi.nlm.nih.gov/pubmed/27827433 http://dx.doi.org/10.1038/srep36527 |
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author | Yi, Hyojeong Choi, Jin Myung Hwang, Junghyun Prati, Fabio Cao, Thinh-Phat Lee, Sung Haeng Kim, Heenam Stanley |
author_facet | Yi, Hyojeong Choi, Jin Myung Hwang, Junghyun Prati, Fabio Cao, Thinh-Phat Lee, Sung Haeng Kim, Heenam Stanley |
author_sort | Yi, Hyojeong |
collection | PubMed |
description | The omega loop in β-lactamases plays a pivotal role in substrate recognition and catalysis, and some mutations in this loop affect the adaptability of the enzymes to new antibiotics. Various mutations, including substitutions, deletions, and intragenic duplications resulting in tandem repeats (TRs), have been associated with β-lactamase substrate spectrum extension. TRs are unique among the mutations as they cause severe structural perturbations in the enzymes. We explored the process by which TRs are accommodated in order to test the adaptability of the omega loop. Structures of the mutant enzymes showed that the extra amino acid residues in the omega loop were freed outward from the enzyme, thereby maintaining the overall enzyme integrity. This structural adjustment was accompanied by disruptions of the internal α-helix and hydrogen bonds that originally maintained the conformation of the omega loop and the active site. Consequently, the mutant enzymes had a relaxed binding cavity, allowing for access of new substrates, which regrouped upon substrate binding in an induced-fit manner for subsequent hydrolytic reactions. Together, the data demonstrate that the design of the binding cavity, including the omega loop with its enormous adaptive capacity, is the foundation of the continuous evolution of β-lactamases against new drugs. |
format | Online Article Text |
id | pubmed-5101513 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-51015132016-11-14 High adaptability of the omega loop underlies the substrate-spectrum-extension evolution of a class A β-lactamase, PenL Yi, Hyojeong Choi, Jin Myung Hwang, Junghyun Prati, Fabio Cao, Thinh-Phat Lee, Sung Haeng Kim, Heenam Stanley Sci Rep Article The omega loop in β-lactamases plays a pivotal role in substrate recognition and catalysis, and some mutations in this loop affect the adaptability of the enzymes to new antibiotics. Various mutations, including substitutions, deletions, and intragenic duplications resulting in tandem repeats (TRs), have been associated with β-lactamase substrate spectrum extension. TRs are unique among the mutations as they cause severe structural perturbations in the enzymes. We explored the process by which TRs are accommodated in order to test the adaptability of the omega loop. Structures of the mutant enzymes showed that the extra amino acid residues in the omega loop were freed outward from the enzyme, thereby maintaining the overall enzyme integrity. This structural adjustment was accompanied by disruptions of the internal α-helix and hydrogen bonds that originally maintained the conformation of the omega loop and the active site. Consequently, the mutant enzymes had a relaxed binding cavity, allowing for access of new substrates, which regrouped upon substrate binding in an induced-fit manner for subsequent hydrolytic reactions. Together, the data demonstrate that the design of the binding cavity, including the omega loop with its enormous adaptive capacity, is the foundation of the continuous evolution of β-lactamases against new drugs. Nature Publishing Group 2016-11-09 /pmc/articles/PMC5101513/ /pubmed/27827433 http://dx.doi.org/10.1038/srep36527 Text en Copyright © 2016, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Yi, Hyojeong Choi, Jin Myung Hwang, Junghyun Prati, Fabio Cao, Thinh-Phat Lee, Sung Haeng Kim, Heenam Stanley High adaptability of the omega loop underlies the substrate-spectrum-extension evolution of a class A β-lactamase, PenL |
title | High adaptability of the omega loop underlies the substrate-spectrum-extension evolution of a class A β-lactamase, PenL |
title_full | High adaptability of the omega loop underlies the substrate-spectrum-extension evolution of a class A β-lactamase, PenL |
title_fullStr | High adaptability of the omega loop underlies the substrate-spectrum-extension evolution of a class A β-lactamase, PenL |
title_full_unstemmed | High adaptability of the omega loop underlies the substrate-spectrum-extension evolution of a class A β-lactamase, PenL |
title_short | High adaptability of the omega loop underlies the substrate-spectrum-extension evolution of a class A β-lactamase, PenL |
title_sort | high adaptability of the omega loop underlies the substrate-spectrum-extension evolution of a class a β-lactamase, penl |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5101513/ https://www.ncbi.nlm.nih.gov/pubmed/27827433 http://dx.doi.org/10.1038/srep36527 |
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