6C89

NDM-1 Beta-Lactamase Exhibits Differential Active Site Sequence Requirements for the Hydrolysis of Penicillin versus Carbapenem Antibiotics

Summary for 6C89

• Entry DOI: 10.2210/pdb6c89/pdb
• Descriptor: Beta-lactamase, ZINC ION, 1,2-ETHANEDIOL, ... (7 entities in total)
• Functional Keywords: ndm-1; beta-lactamase; deep sequencing; antibiotic resistance; beta-lactams, antimicrobial protein
• Biological source: Escherichia coli
• Total number of polymer chains: 4
• Total formula weight: 98758.36

Authors

Palzkill, T.,Sun, Z.,Sankaran, B. (deposition date: 2018-01-24, release date: 2018-12-12, Last modification date: 2023-10-04)

Primary citation

Sun, Z.,Hu, L.,Sankaran, B.,Prasad, B.V.V.,Palzkill, T.
Differential active site requirements for NDM-1 beta-lactamase hydrolysis of carbapenem versus penicillin and cephalosporin antibiotics.
Nat Commun, 9:4524-4524, 2018

PubMed Abstract: New Delhi metallo-β-lactamase-1 exhibits a broad substrate profile for hydrolysis of the penicillin, cephalosporin and 'last resort' carbapenems, and thus confers bacterial resistance to nearly all β-lactam antibiotics. Here we address whether the high catalytic efficiency for hydrolysis of these diverse substrates is reflected by similar sequence and structural requirements for catalysis, i.e., whether the same catalytic machinery is used to achieve hydrolysis of each class. Deep sequencing of randomized single codon mutation libraries that were selected for resistance to representative antibiotics reveal stringent sequence requirements for carbapenem versus penicillin or cephalosporin hydrolysis. Further, the residue positions required for hydrolysis of penicillins and cephalosporins are a subset of those required for carbapenem hydrolysis. Thus, while a common core of residues is used for catalysis of all substrates, carbapenem hydrolysis requires an additional set of residues to achieve catalytic efficiency comparable to that for penicillins and cephalosporins.

PubMed: 30375382
DOI: 10.1038/s41467-018-06839-1

Experimental method

X-RAY DIFFRACTION (1.75006148726 Å)