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Verona integron\u2010encoded MBL (VIM) enzymes are among the most clinically important MBLs, with VIM\u20101 increasing in carbapenem\u2010resistant Enterobacteriaceae (<jats:italic>Escherichia coli<\/jats:italic>,<jats:italic> Klebsiella pneumoniae<\/jats:italic>) 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\u20101 and its complexes with a substrate\u2010mimicking thioenolate inhibitor, ML302F, that restores meropenem activity against a range of VIM\u20101 producing clinical strains, and the hydrolysed product of the carbapenem meropenem. Comparison of these two structures identifies a water\u2010mediated 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\u2010bound 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Enzymes<\/jats:title><jats:p>\n<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.chem.qmul.ac.uk\/iubmb\/enzyme\/EC3\/5\/2\/6.html\">EC 3.5.2.6<\/jats:ext-link>\n<\/jats:p><\/jats:sec><jats:sec><jats:title>Databases<\/jats:title><jats:p>Co\u2010ordinates and structure factors for protein structures described in this manuscript have been deposited in the Protein Data Bank (<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.rcsb.org\/pdb\">www.rcsb.org\/pdb<\/jats:ext-link>) with accession codes <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.rcsb.org\/pdb\/search\/structidSearch.do?structureId=5N5G\">5N5G<\/jats:ext-link> (VIM\u20101), <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.rcsb.org\/pdb\/search\/structidSearch.do?structureId=5N5H\">5N5H<\/jats:ext-link> (VIM\u20101:ML302F complex) and <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.rcsb.org\/pdb\/search\/structidSearch.do?structureId=5N5I\">5N5I<\/jats:ext-link> (VIM\u20101\u2010hydrolysed meropenem complex).<\/jats:p><\/jats:sec>","DOI":"10.1111\/febs.14695","type":"journal-article","created":{"date-parts":[[2018,11,15]],"date-time":"2018-11-15T13:44:47Z","timestamp":1542289487000},"page":"169-183","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["Crystal structures of VIM\u20101 complexes explain active site heterogeneity in VIM\u2010class metallo\u2010\u03b2\u2010lactamases"],"prefix":"10.1111","volume":"286","author":[{"given":"Ramya","family":"Salimraj","sequence":"first","affiliation":[{"name":"School of Cellular and Molecular Medicine University of Bristol UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip","family":"Hinchliffe","sequence":"additional","affiliation":[{"name":"School of Cellular and Molecular Medicine University of Bristol UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magda","family":"Kosmopoulou","sequence":"additional","affiliation":[{"name":"School of Cellular and Molecular Medicine University of Bristol UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan M.","family":"Tyrrell","sequence":"additional","affiliation":[{"name":"Institute of Infection and Immunity Cardiff University UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00fcrgen","family":"Brem","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sander S.","family":"van Berkel","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anil","family":"Verma","sequence":"additional","affiliation":[{"name":"Oxford Protein Production Facility UK Rutherford Appleton Laboratory Oxfordshire UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raymond J.","family":"Owens","sequence":"additional","affiliation":[{"name":"Oxford Protein Production Facility UK Rutherford Appleton Laboratory Oxfordshire UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A.","family":"McDonough","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy R.","family":"Walsh","sequence":"additional","affiliation":[{"name":"Institute of Infection and Immunity Cardiff University 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