6kw1 | pdb_00006kw1

The structure of the metallo-beta-lactamase VIM-2 in complex with a triazolylthioacetamide 1b

spinqualitylabelsall models 6kw1, resolution 1.78Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6kw1 is a 2 chain structure with sequence from "bacillus_aeruginosus"_(schroeter_1872)_trevisan_1885 "bacillus aeruginosus" (schroeter 1872) trevisan 1885. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 9RX, ACT, CL, FMT, MG, NA, ZN Gene: blaVIM-2, bla vim-2, bla-VIM-2, blasVIM-2, blaVIM2, VIM-2, vim-2, IPC669_36195 ("Bacillus aeruginosus" (Schroeter 1872) Trevisan 1885) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Inhibition of beta-lactamases presents a promising strategy to restore the beta-lactams antibacterial activity to resistant bacteria. In this work, we found that aromatic carboxyl substituted 2-triazolylthioacetamides 1a-j inhibited VIM-2, exhibiting an IC50 value in the range of 20.6-58.6 muM. The structure-activity relationship study revealed that replacing the aliphatic carboxylic acid with aromatic carboxyl improved the inhibitory activity of 2-triazolylthioacetamides against VIM-2. 1a-j (16 mg/mL) restored the antibacterial activity of cefazolin against E. coli cell expressing VIM-2, resulting in a 4-8-fold reduction in MICs. The isothermal titration calorimetry (ITC) characterization suggested that the primary binding 2-triazolylthioacetamide (1b, 1c, or 1h) to VIM-2 was a combination of entropy and enthalpy contributions. Further, the crystal structure of VIM-2 in complex with 1b was obtained by co-crystallization with a hanging-drop vapour-diffusion method. The crystal structure analysis revealed that 1b bound to two Zn(II) ions of the enzyme active sites, formed H-bound with Asn233 and structure water molecule, and interacted with the hydrophobic pocket of enzyme activity center utilizing hydrophobic moieties; especially for the phenyl of aromatic carboxyl which formed pi-pi stacking with active residue His263. These studies confirmed that aromatic carboxyl substituted 2-triazolylthioacetamides are the potent VIM-2 inhibitors scaffold and provided help to further optimize 2-triazolylthioacetamides as VIM-2 even or broad-spectrum MbetaLs inhibitors. Kinetic, Thermodynamic, and Crystallographic Studies of 2-Triazolylthioacetamides as Verona Integron-Encoded Metallo-beta-Lactamase 2 (VIM-2) Inhibitor.,Xiang Y, Zhang YJ, Ge Y, Zhou Y, Chen C, Wahlgren WY, Tan X, Chen X, Yang KW Biomolecules. 2020 Jan 1;10(1). pii: biom10010072. doi: 10.3390/biom10010072. PMID:31906402 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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