The search for new drugs against Streptococcus pneumoniae (pneumococcus) is driven by the 1.5 million deaths it causes annually. Choline-binding proteins attach to the pneumococcal cell wall through domains that recognize choline moieties, and their involvement in pneumococcal virulence makes them potential targets for drug development. We have defined chemical criteria involved in the docking of small molecules from a three-dimensional structural library to the major pneumococcal autolysin (LytA) choline binding domain. These criteria were used to identify compounds that could interfere with the attachment of this protein to the cell wall, and several quinolones that fit this framework were found to inhibit the cell wall-degrading activity of LytA. Furthermore, these compounds produced similar effects on other enzymes with different catalytic activities but that contained a similar choline binding domain; that is, autolysin (LytC) and the phage lytic enzyme (Cpl-1). Finally, we resolved the crystal structure of the complex between the choline binding domain of LytA and ofloxacin at a resolution of 2.6 Angstroms. These data constitute an important launch pad from which effective drugs to combat pneumococcal infections can be developed.
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http://dx.doi.org/10.1074/jbc.M501236200 | DOI Listing |
ACS Appl Mater Interfaces
December 2024
Key Laboratory of Polyoxometalate and Reticular Material Chemistry of Ministry of Education, School of Chemistry, Northeast Normal University, Changchun 130024, China.
Liposomes have attracted attention in biomedicine and pharmacy for their benefits including reduced toxicity, extended pharmacokinetics, and biocompatibility. However, their limitations include susceptibility to blood clearance, rapid disintegration, and lack of functionality, restricting their further applications. To address these challenges, inspired by the unique topological features of cyclic polymers and the specific binding property of the choline phosphate (CP) lipid, dipole-dipole interactions between CP molecules are utilized to create a detachable cyclic PEG-embedded CP liposome (d-cycPEG-lipo).
View Article and Find Full Text PDFFood Chem
December 2024
School of Chemical Engineering, Sichuan University, Chengdu 610065, China. Electronic address:
FeO is a cost-effective and strong magnetic core, meanwhile polymerizable deep eutectic solvents (PDESs) are considered to have excellent performance and biocompatibility in separation and material fields. Therefore, the aim was to prepare magnetic microspheres (P(DES-co-St)@FeO) with FeO as the core and PDESs (choline chloride/acrylic acid, 1:2; choline chloride/itaconic acid, 1:1)-styrene (St) copolymer as the shell for binding of target protein. The resulting microspheres exhibited ideal magnetic responsiveness (14.
View Article and Find Full Text PDFFront Vet Sci
December 2024
College of Medicine, Yichun University, Yichun, China.
serotype 2 ( type 2, SS2) is one of the zoonotic pathogens known to induce meningitis, septicemia, and arthritis in both pigs and humans, resulting in public health concerns. CbpD, also termed CrfP, is one of the choline-binding proteins (CBPs) that was found as a murein hydrolase in SS2 and plays crucial roles in natural genetic transformation under the control of ComRS-ComX regulatory system by a previous study. Nonetheless, the possible functions of CbpD in virulence and pathogenesis in SS2 remain unclear.
View Article and Find Full Text PDFPestic Biochem Physiol
December 2024
Key Laboratory of Integrated Management of Crop Diseases and Pests (Ministry of Education), College of Plant Protection, Nanjing Agricultural University, Nanjing 210095, China. Electronic address:
Choline acetyltransferase (ChAT) is crucial for acetylcholine synthesis and regulates diverse functions in numerous biological processes. Omeprazole, an inhibitor on human ChAT, was evaluated here on insect ChAT as a potential inhibitor, as well as its insecticidal potency on Nilaparvata lugens, a major insect pest on rice. The evaluation also included omeprazole analogs and α-NETA, in order to explore a superior leading compound targeting on insect ChAT.
View Article and Find Full Text PDFStructure
November 2024
Key Laboratory of Biomacromolecules (CAS), National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address:
In cholinergic neurons, choline is the precursor of the excitatory neurotransmitter acetylcholine (ACh), which plays a fundamental role in the brain. The high-affinity choline transporter, CHT1, mediates the efficient recycling of choline to facilitate ACh synthesis in the presynapse. Here, we report high-resolution cryoelectron microscopic (cryo-EM) structures of CHT1 in complex with the inhibitors HC-3 and ML352, the substrate choline, and a substrate-free state.
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