Kinetic and structural characterization of the first B3 metallo-β-lactamase with an active-site glutamic acid
The structural diversity in metallo-β-lactamases (MBLs), especially in the vicinity of the active site, has been a major hurdle in the development of clinically effective inhibitors. Representatives from three variants of the B3 MBL subclass, containing either the canonical HHH/DHH active-site motif...
| Main Authors: | , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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American Society for Microbiology
2021
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| _version_ | 1826296801644249088 |
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| author | Wilson, LA Knaven, EG Morris, MT Monteiro Pedroso, M Schofield, CJ Brück, TB Boden, M Waite, DW Hugenholtz, P Guddat, L Schenk, G |
| author_facet | Wilson, LA Knaven, EG Morris, MT Monteiro Pedroso, M Schofield, CJ Brück, TB Boden, M Waite, DW Hugenholtz, P Guddat, L Schenk, G |
| author_sort | Wilson, LA |
| collection | OXFORD |
| description | The structural diversity in metallo-β-lactamases (MBLs), especially in the vicinity of the active site, has been a major hurdle in the development of clinically effective inhibitors. Representatives from three variants of the B3 MBL subclass, containing either the canonical HHH/DHH active-site motif (present in the majority of MBLs in this subclass) or the QHH/DHH (B3-Q) or HRH/DQK (B3-RQK) variations, were reported previously. Here, we describe the structure and kinetic properties of the first example (SIE-1) of a fourth variant containing the EHH/DHH active-site motif (B3-E). SIE-1 was identified in the hexachlorocyclohexane-degrading bacterium Sphingobium indicum, and kinetic analyses demonstrate that although it is active against a wide range of antibiotics, its efficiency is lower than that of other B3 MBLs but has increased efficiency toward cephalosporins relative to other β-lactam substrates. The overall fold of SIE-1 is characteristic of the MBLs; the notable variation is observed in the Zn1 site due to the replacement of the canonical His116 by a glutamate. The unusual preference of SIE-1 for cephalosporins and its occurrence in a widespread environmental organism suggest the scope for increased MBL-mediated β-lactam resistance. Thus, it is relevant to include SIE-1 in MBL inhibitor design studies to widen the therapeutic scope of much needed antiresistance drugs.
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| first_indexed | 2024-03-07T04:21:56Z |
| format | Journal article |
| id | oxford-uuid:cb4e0f1c-deee-448b-9047-afe7862e9e85 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T04:21:56Z |
| publishDate | 2021 |
| publisher | American Society for Microbiology |
| record_format | dspace |
| spelling | oxford-uuid:cb4e0f1c-deee-448b-9047-afe7862e9e852022-03-27T07:13:58ZKinetic and structural characterization of the first B3 metallo-β-lactamase with an active-site glutamic acidJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:cb4e0f1c-deee-448b-9047-afe7862e9e85EnglishSymplectic ElementsAmerican Society for Microbiology2021Wilson, LAKnaven, EGMorris, MTMonteiro Pedroso, MSchofield, CJBrück, TBBoden, MWaite, DWHugenholtz, PGuddat, LSchenk, GThe structural diversity in metallo-β-lactamases (MBLs), especially in the vicinity of the active site, has been a major hurdle in the development of clinically effective inhibitors. Representatives from three variants of the B3 MBL subclass, containing either the canonical HHH/DHH active-site motif (present in the majority of MBLs in this subclass) or the QHH/DHH (B3-Q) or HRH/DQK (B3-RQK) variations, were reported previously. Here, we describe the structure and kinetic properties of the first example (SIE-1) of a fourth variant containing the EHH/DHH active-site motif (B3-E). SIE-1 was identified in the hexachlorocyclohexane-degrading bacterium Sphingobium indicum, and kinetic analyses demonstrate that although it is active against a wide range of antibiotics, its efficiency is lower than that of other B3 MBLs but has increased efficiency toward cephalosporins relative to other β-lactam substrates. The overall fold of SIE-1 is characteristic of the MBLs; the notable variation is observed in the Zn1 site due to the replacement of the canonical His116 by a glutamate. The unusual preference of SIE-1 for cephalosporins and its occurrence in a widespread environmental organism suggest the scope for increased MBL-mediated β-lactam resistance. Thus, it is relevant to include SIE-1 in MBL inhibitor design studies to widen the therapeutic scope of much needed antiresistance drugs. |
| spellingShingle | Wilson, LA Knaven, EG Morris, MT Monteiro Pedroso, M Schofield, CJ Brück, TB Boden, M Waite, DW Hugenholtz, P Guddat, L Schenk, G Kinetic and structural characterization of the first B3 metallo-β-lactamase with an active-site glutamic acid |
| title | Kinetic and structural characterization of the first B3 metallo-β-lactamase with an active-site glutamic acid |
| title_full | Kinetic and structural characterization of the first B3 metallo-β-lactamase with an active-site glutamic acid |
| title_fullStr | Kinetic and structural characterization of the first B3 metallo-β-lactamase with an active-site glutamic acid |
| title_full_unstemmed | Kinetic and structural characterization of the first B3 metallo-β-lactamase with an active-site glutamic acid |
| title_short | Kinetic and structural characterization of the first B3 metallo-β-lactamase with an active-site glutamic acid |
| title_sort | kinetic and structural characterization of the first b3 metallo β lactamase with an active site glutamic acid |
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