Abstract
LicA plays a key role in the cell-wall phosphorylcholine biosynthesis of Streptococcus pneumonia. Here we determined the crystal structures of apo-form LicA at 1.94 Å and two complex forms LicA-choline and LicA-AMP-MES, at 2.01 and 1.45 Å resolution, respectively. The overall structure adopts a canonical protein kinase-like fold, with the active site located in the crevice of the N- and C- terminal domains. The three structures present distinct poses of the active site, which undergoes an open-closed-open conformational change upon substrate binding and product release. The structure analyses combined with mutageneses and enzymatic assays enabled us to figure out the key residues for the choline kinase activity of LicA. In addition, structural comparison revealed the loop between helices α7 and α8 might modulate the substrate specificity and catalytic activity. These findings shed light on the structure and mechanism of the prokaryotic choline kinase LicA, and might direct the rational design of novel anti-pneumococcal drugs.
Highlights
The Gram-positive pathogen Streptococcus pneumoniae, is a major cause of human pneumonia, meningitis, bacteremia, otitis media and sinusitis [1, 2]
A series of choline-binding proteins (CBPs), which are non-covalent linked to the phosphorylcholine of cell wall, are involved in bacterial growth, cell division and pathogenesis
LicA exists as a monomer in solution, which was confirmed by gel-filtration chromatography (S1 Fig.)
Summary
The Gram-positive pathogen Streptococcus pneumoniae, is a major cause of human pneumonia, meningitis, bacteremia, otitis media and sinusitis [1, 2]. Structural analysis combined with mutageneses and enzymatic assays enabled us to assign the key residues for the choline kinase activity of LicA. Structural comparison of LicA with its human homolog revealed that insertion or deletion of an active-site loop differs the activity of eukaryotic and prokaryotic choline kinases.
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