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Crystal structures of VIM‐1 complexes explain active site heterogeneity in VIM‐class metallo‐β‐lactamases
Ramya Salimraj,
Philip Hinchliffe,
Magda Kosmopoulou,
Jon Tyrrell 
,
Jürgen Brem,
Sander S. van Berkel,
Anil Verma,
Raymond J. Owens,
Michael A. McDonough,
Timothy R. Walsh,
Christopher J. Schofield,
James Spencer
,
Jürgen Brem,
Sander S. van Berkel,
Anil Verma,
Raymond J. Owens,
Michael A. McDonough,
Timothy R. Walsh,
Christopher J. Schofield,
James Spencer
The FEBS Journal, Volume: 286, Issue: 1, Pages: 169 - 183
Swansea University Author:
Jon Tyrrell
-
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© 2018 The Authors. This is an open access article under the terms of the Creative Commons Attribution License.
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DOI (Published version): 10.1111/febs.14695
Abstract
Metallo-β-Lactamases (MBLs) protect bacteria from almost all β-lactam antibiotics. Verona integron-encoded MBL (VIM) enzymes are among the most clinically important MBLs, with VIM-1 increasing in carbapenem-resistant Enterobacteriaceae (Escherichia coli, Klebsiella pneumoniae) that are among the har...
| Published in: | The FEBS Journal |
|---|---|
| ISSN: | 1742-464X 1742-4658 |
| Published: |
Wiley
2019
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| Online Access: |
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| URI: | https://cronfa.swan.ac.uk/Record/cronfa70427 |
| first_indexed |
2025-09-21T22:01:41Z |
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2025-10-17T09:30:55Z |
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2025-10-16T15:20:43.3117666 v2 70427 2025-09-21 Crystal structures of VIM‐1 complexes explain active site heterogeneity in VIM‐class metallo‐β‐lactamases ad510c73555adf718387af219e235a6e 0000-0001-8565-2590 Jon Tyrrell Jon Tyrrell true false 2025-09-21 MEDS Metallo-β-Lactamases (MBLs) protect bacteria from almost all β-lactam antibiotics. Verona integron-encoded MBL (VIM) enzymes are among the most clinically important MBLs, with VIM-1 increasing in carbapenem-resistant Enterobacteriaceae (Escherichia coli, Klebsiella pneumoniae) that are among the hardest bacterial pathogens to treat. VIM enzymes display sequence variation at residues (224 and 228) that in related MBLs are conserved and participate in substrate binding. How they accommodate this variability, while retaining catalytic efficiency against a broad substrate range, has remained unclear. Here, we present crystal structures of VIM-1 and its complexes with a substrate-mimicking thioenolate inhibitor, ML302F, that restores meropenem activity against a range of VIM-1 producing clinical strains, and the hydrolysed product of the carbapenem meropenem. Comparison of these two structures identifies a water-mediated hydrogen bond, between the carboxylate group of substrate/inhibitor and the backbone carbonyl of the active site zinc ligand Cys221, that is common to both complexes. Structural comparisons show that the responsible Cys221-bound water is observed in all known VIM structures, participates in carboxylate binding with other inhibitor classes, and thus effectively replicates the role of the conserved Lys224 in analogous complexes with other MBLs. These results provide a mechanism for substrate binding that permits the variation at positions 224 and 228 that is a hallmark of VIM MBLs. Journal Article The FEBS Journal 286 1 169 183 Wiley 1742-464X 1742-4658 antibiotic resistance; carbapenem; metallo-β-lactamase; VIM; X-ray crystallography 1 1 2019 2019-01-01 10.1111/febs.14695 COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University Another institution paid the OA fee Medical Research Council. Grant Numbers: MR/K018779/1, MR/N002679/1; FP7 Joint Technology Initiatives. Grant Number: 115583; National Institute of Allergy and Infectious Diseases. Grant Number: R01AI100560 2025-10-16T15:20:43.3117666 2025-09-21T18:13:40.1578003 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Ramya Salimraj 1 Philip Hinchliffe 2 Magda Kosmopoulou 3 Jon Tyrrell 0000-0001-8565-2590 4 Jürgen Brem 5 Sander S. van Berkel 6 Anil Verma 7 Raymond J. Owens 8 Michael A. McDonough 9 Timothy R. Walsh 10 Christopher J. Schofield 11 James Spencer 12 70427__35370__098b278fd81848e8841e474f39b2b961.pdf 70427.VoR.pdf 2025-10-16T15:14:05.6826387 Output 1736071 application/pdf Version of Record true © 2018 The Authors. This is an open access article under the terms of the Creative Commons Attribution License. true eng http://creativecommons.org/licenses/by/4.0/ |
| title |
Crystal structures of VIM‐1 complexes explain active site heterogeneity in VIM‐class metallo‐β‐lactamases |
| spellingShingle |
Crystal structures of VIM‐1 complexes explain active site heterogeneity in VIM‐class metallo‐β‐lactamases Jon Tyrrell |
| title_short |
Crystal structures of VIM‐1 complexes explain active site heterogeneity in VIM‐class metallo‐β‐lactamases |
| title_full |
Crystal structures of VIM‐1 complexes explain active site heterogeneity in VIM‐class metallo‐β‐lactamases |
| title_fullStr |
Crystal structures of VIM‐1 complexes explain active site heterogeneity in VIM‐class metallo‐β‐lactamases |
| title_full_unstemmed |
Crystal structures of VIM‐1 complexes explain active site heterogeneity in VIM‐class metallo‐β‐lactamases |
| title_sort |
Crystal structures of VIM‐1 complexes explain active site heterogeneity in VIM‐class metallo‐β‐lactamases |
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ad510c73555adf718387af219e235a6e |
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ad510c73555adf718387af219e235a6e_***_Jon Tyrrell |
| author |
Jon Tyrrell |
| author2 |
Ramya Salimraj Philip Hinchliffe Magda Kosmopoulou Jon Tyrrell Jürgen Brem Sander S. van Berkel Anil Verma Raymond J. Owens Michael A. McDonough Timothy R. Walsh Christopher J. Schofield James Spencer |
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Wiley |
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Metallo-β-Lactamases (MBLs) protect bacteria from almost all β-lactam antibiotics. Verona integron-encoded MBL (VIM) enzymes are among the most clinically important MBLs, with VIM-1 increasing in carbapenem-resistant Enterobacteriaceae (Escherichia coli, Klebsiella pneumoniae) that are among the hardest bacterial pathogens to treat. VIM enzymes display sequence variation at residues (224 and 228) that in related MBLs are conserved and participate in substrate binding. How they accommodate this variability, while retaining catalytic efficiency against a broad substrate range, has remained unclear. Here, we present crystal structures of VIM-1 and its complexes with a substrate-mimicking thioenolate inhibitor, ML302F, that restores meropenem activity against a range of VIM-1 producing clinical strains, and the hydrolysed product of the carbapenem meropenem. Comparison of these two structures identifies a water-mediated hydrogen bond, between the carboxylate group of substrate/inhibitor and the backbone carbonyl of the active site zinc ligand Cys221, that is common to both complexes. Structural comparisons show that the responsible Cys221-bound water is observed in all known VIM structures, participates in carboxylate binding with other inhibitor classes, and thus effectively replicates the role of the conserved Lys224 in analogous complexes with other MBLs. These results provide a mechanism for substrate binding that permits the variation at positions 224 and 228 that is a hallmark of VIM MBLs. |
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2019-01-01T05:30:51Z |
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11.089386 |