8xm3

Methionyl-tRNA synthetase from Staphylococcus aureus complexed with a chlorhexidine derivative and ATP

spinqualitylabelsall models 8xm3, resolution 1.92Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8xm3 is a 1 chain structure with sequence from Staphylococcus aureus subsp. aureus COL. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.92Å Ligands: A1LV5, ATP Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function SYM_STAAC Is required not only for elongation of protein synthesis but also for the initiation of all mRNA translation through initiator tRNA(fMet) aminoacylation. Publication Abstract from PubMed Methionyl-tRNA synthetase (MetRS) catalyzes the attachment of l-methionine (l-Met) to tRNA(Met) to generate methionyl-tRNA(Met), an essential substrate for protein translation within ribosome. Owing to its indispensable biological function and the structural discrepancies with human counterpart, bacterial MetRS is considered an ideal target for developing antibacterials. Herein, chlorhexidine (CHX) was identified as a potent binder of Staphylococcus aureus MetRS (SaMetRS) through an ATP-aided affinity screening. The co-crystal structure showed that CHX simultaneously occupies the enlarged l-Met pocket (EMP) and the auxiliary pocket (AP) of SaMetRS with its two chlorophenyl groups, while its central hexyl linker swings upwards to interact with some conserved hydrophobic residues. ATP adopts alternative conformations in the active site cavity, and forms ionic bonds and water-mediated hydrogen bonds with CHX. Consistent with this synergistic binding mode, ATP concentration-dependently enhanced the binding affinity of CHX to SaMetRS from 10.2 muM (no ATP) to 0.45 muM (1 mM ATP). While it selectively inhibited two representative type 1 MetRSs from S. aureus and Enterococcus faecalis, CHX did not show significant interactions with three tested type 2 MetRSs, including human cytoplasmic MetRS, in the enzyme inhibition and biophysical binding assays, probably due to the conformational differences between two types of MetRSs at their EMP and AP. Our findings on CHX may inspire the design of MetRS-directed antimicrobials in future. Biochemical and structural characterization of chlorhexidine as an ATP-assisted inhibitor against type 1 methionyl-tRNA synthetase from Gram-positive bacteria.,Lu F, Xia K, Su J, Yi J, Luo Z, Xu J, Gu Q, Chen B, Zhou H Eur J Med Chem. 2024 Mar 15;268:116303. doi: 10.1016/j.ejmech.2024.116303. Epub , 2024 Mar 4. PMID:38458107 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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