6V7I

Structure of KPC-2 bound to Vaborbactam at 1.25 A

Summary for 6V7I

• Entry DOI: 10.2210/pdb6v7i/pdb
• Descriptor: Carbapenem-hydrolyzing beta-lactamase KPC, Vaborbactam, SULFATE ION, ... (5 entities in total)
• Functional Keywords: carbapenemase, boronate, beta-lactamase, inhibitor, hydrolase
• Biological source: Klebsiella pneumoniae
• Total number of polymer chains: 1
• Total formula weight: 31580.11

Authors

Pemberton, O.A.,Chen, Y. (deposition date: 2019-12-08, release date: 2020-08-12, Last modification date: 2023-10-11)

Primary citation

Pemberton, O.A.,Tsivkovski, R.,Totrov, M.,Lomovskaya, O.,Chen, Y.
Structural Basis and Binding Kinetics of Vaborbactam in Class A beta-Lactamase Inhibition.
Antimicrob.Agents Chemother., 64:-, 2020

PubMed Abstract: Class A β-lactamases are a major cause of β-lactam resistance in Gram-negative bacteria. The recently FDA-approved cyclic boronate vaborbactam is a reversible covalent inhibitor of class A β-lactamases, including CTX-M extended-spectrum β-lactamase and KPC carbapenemase, both frequently observed in the clinic. Intriguingly, vaborbactam displayed different binding kinetics and cell-based activity for these two enzymes, despite their similarity. A 1.0-Å crystal structure of CTX-M-14 demonstrated that two catalytic residues, K73 and E166, are positively charged and neutral, respectively. Meanwhile, a 1.25-Å crystal structure of KPC-2 revealed a more compact binding mode of vaborbactam versus CTX-M-14, as well as alternative conformations of W105. Together with kinetic analysis of W105 mutants, the structures demonstrate the influence of this residue and the unusual conformation of the β3 strand on the inactivation rate, as well as the stability of the reversible covalent bond with S70. Furthermore, studies of KPC-2 S130G mutant shed light on the different impacts of S130 in the binding of vaborbactam versus avibactam, another recently approved β-lactamase inhibitor. Taken together, these new data provide valuable insights into the inhibition mechanism of vaborbactam and future development of cyclic boronate inhibitors.

PubMed: 32778546
DOI: 10.1128/AAC.00398-20

Experimental method

X-RAY DIFFRACTION (1.25 Å)