6R73

Structure of IMP-13 metallo-beta-lactamase complexed with hydrolysed meropenem

6R73 の概要

• エントリーDOI: 10.2210/pdb6r73/pdb
• 分子名称: Beta-lactamase, (2~{S},3~{R},4~{S})-2-[(2~{S},3~{R})-1,3-bis(oxidanyl)-1-oxidanylidene-butan-2-yl]-4-[(3~{S},5~{S})-5-(dimethylcarbamoy l)pyrrolidin-3-yl]sulfanyl-3-methyl-3,4-dihydro-2~{H}-pyrrole-5-carboxylic acid, ZINC ION, ... (4 entities in total)
• 機能のキーワード: metallo-beta-lactamase, zinc-binding protein, antibiotic resistance, hydrolase
• 由来する生物種: Pseudomonas aeruginosa
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 51285.66

構造登録者

Softley, C.A.,Zak, K.,Kolonko, M.,Sattler, M.,Popowicz, G. (登録日: 2019-03-28, 公開日: 2020-03-25, 最終更新日: 2024-11-13)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.3 Å)