6R79

Structure of IMP-13 metallo-beta-lactamase in apo form (loop open)

Summary for 6R79

• Entry DOI: 10.2210/pdb6r79/pdb
• Related: 6R78
• Descriptor: Beta-lactamase, GLYCEROL, BETA-MERCAPTOETHANOL, ... (8 entities in total)
• Functional Keywords: metallo-beta-lactamase beta-lactamase, hydrolase
• Biological source: Pseudomonas aeruginosa
• Total number of polymer chains: 4
• Total formula weight: 100906.48

Authors

Zak, K.M.,Softley, C.,Kolonko, M.,Sattler, M.,Popowicz, G.M. (deposition date: 2019-03-28, release date: 2020-04-01, Last modification date: 2024-01-24)

Primary citation

Softley, C.A.,Zak, K.M.,Bostock, M.J.,Fino, R.,Zhou, R.X.,Kolonko, M.,Mejdi-Nitiu, R.,Meyer, H.,Sattler, M.,Popowicz, G.M.
Structure and Molecular Recognition Mechanism of IMP-13 Metallo-beta-Lactamase.
Antimicrob.Agents Chemother., 64:-, 2020

PubMed Abstract: Multidrug resistance among Gram-negative bacteria is a major global public health threat. Metallo-β-lactamases (MBLs) target the most widely used antibiotic class, the β-lactams, including the most recent generation of carbapenems. Interspecies spread renders these enzymes a serious clinical threat, and there are no clinically available inhibitors. We present the crystal structures of IMP-13, a structurally uncharacterized MBL from the Gram-negative bacterium found in clinical outbreaks globally, and characterize the binding using solution nuclear magnetic resonance spectroscopy and molecular dynamics simulations. The crystal structures of apo IMP-13 and IMP-13 bound to four clinically relevant carbapenem antibiotics (doripenem, ertapenem, imipenem, and meropenem) are presented. Active-site plasticity and the active-site loop, where a tryptophan residue stabilizes the antibiotic core scaffold, are essential to the substrate-binding mechanism. The conserved carbapenem scaffold plays the most significant role in IMP-13 binding, explaining the broad substrate specificity. The observed plasticity and substrate-locking mechanism provide opportunities for rational drug design of novel metallo-β-lactamase inhibitors, essential in the fight against antibiotic resistance.

PubMed: 32205343
DOI: 10.1128/AAC.00123-20

Experimental method

X-RAY DIFFRACTION (1.9 Å)