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Lumazine Synthase (lumazine + synthase)
Selected AbstractsImprovement of the quality of lumazine synthase crystals by protein engineeringACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 7 2008Lidia Rodríguez-Fernández Icosahedral macromolecules have a wide spectrum of potential nanotechnological applications, the success of which relies on the level of accuracy at which the molecular structure is known. Lumazine synthase from Bacillus subtilis forms a 150,Å icosahedral capsid consisting of 60 subunits and crystallizes in space group P6322 or C2. However, the quality of these crystals is poor and structural information is only available at 2.4,Å resolution. As classical strategies for growing better diffracting crystals have so far failed, protein engineering has been employed in order to improve the overexpression and purification of the molecule as well as to obtain new crystal forms. Two cysteines were replaced to bypass misfolding problems and a charged surface residue was replaced to force different molecular packings. The mutant protein crystallizes in space group R3, with unit-cell parameters a = b = 313.02, c = 365.77,Å, , = , = 90.0, , = 120°, and diffracts to 1.6,Å resolution. [source] Structural and thermodynamic insights into the binding mode of five novel inhibitors of lumazine synthase from Mycobacterium tuberculosisFEBS JOURNAL, Issue 20 2006Ekaterina Morgunova Recently published genomic investigations of the human pathogen Mycobacterium tuberculosis have revealed that genes coding the proteins involved in riboflavin biosynthesis are essential for the growth of the organism. Because the enzymes involved in cofactor biosynthesis pathways are not present in humans, they appear to be promising candidates for the development of therapeutic drugs. The substituted purinetrione compounds have demonstrated high affinity and specificity to lumazine synthase, which catalyzes the penultimate step of riboflavin biosynthesis in bacteria and plants. The structure of M. tuberculosis lumazine synthase in complex with five different inhibitor compounds is presented, together with studies of the binding reactions by isothermal titration calorimetry. The inhibitors showed the association constants in the micromolar range. The analysis of the structures demonstrated the specific features of the binding of different inhibitors. The comparison of the structures and binding modes of five different inhibitors allows us to propose the ribitylpurinetrione compounds with C4,C5 alkylphosphate chains as most promising leads for further development of therapeutic drugs against M. tuberculosis. [source] Structural study and thermodynamic characterization of inhibitor binding to lumazine synthase from Bacillus anthracisACTA CRYSTALLOGRAPHICA SECTION D, Issue 9 2010Ekaterina Morgunova The crystal structure of lumazine synthase from Bacillus anthracis was solved by molecular replacement and refined to Rcryst = 23.7% (Rfree = 28.4%) at a resolution of 3.5,Å. The structure reveals the icosahedral symmetry of the enzyme and specific features of the active site that are unique in comparison with previously determined orthologues. The application of isothermal titration calorimetry in combination with enzyme kinetics showed that three designed pyrimidine derivatives bind to lumazine synthase with micromolar dissociation constants and competitively inhibit the catalytic reaction. Structure-based modelling suggested the binding modes of the inhibitors in the active site and allowed an estimation of the possible contacts formed upon binding. The results provide a structural framework for the design of antibiotics active against B. anthracis. [source] | ||||||||||