1w29

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spinqualitylabelsall models 1w29, resolution 2.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

LUMAZINE SYNTHASE FROM MYCOBACTERIUM TUBERCULOSIS BOUND TO 3-(1,3,7-TRIHYDRO-9-D-RIBITYL-2,6,8-PURINETRIONE-7-YL) BUTANE 1-PHOSPHATE

Overview

The enzymes involved in the biosynthesis of riboflavin represent, attractive targets for the development of drugs against bacterial, pathogens, because the inhibitors of these enzymes are not likely to, interfere with enzymes of the mammalian metabolism. Lumazine synthase, catalyzes the penultimate step in the riboflavin biosynthesis pathway. A, number of substituted purinetrione compounds represent a new class of, highly specific inhibitors of lumazine synthase from Mycobacterium, tuberculosis. To develop potent antibiotics for the treatment of, tuberculosis, we have determined the structure of lumazine synthase from, M. tuberculosis in complex with two purinetrione inhibitors and have, studied binding via isothermal titration calorimetry. The structures were, determined by molecular replacement using lumazine synthase from, Saccharomyces cerevisiae as a search model and refined at 2 and 2.3 A, resolution. The R-factors were 14.7 and 17.4%, respectively, and the, R(free) values were 19.3 and 26.3%, respectively. The enzyme was found to, be a pentamer consisting of five subunits related by 5-fold local, symmetry. The comparison of the active site architecture with the active, site of previously determined lumazine synthase structures reveals a, largely conserved topology with the exception of residues Gln141 and, Glu136, which participate in different charge-charge interactions in the, core space of the active site. The impact of structural changes in the, active site on the altered binding and catalytic properties of the enzyme, is discussed. Isothermal titration calorimetry measurements indicate, highly specific binding of the purinetrione inhibitors to the M., tuberculosis enzyme with dissociation constants in micromolar range.

About this Structure

1W29 is a Single protein structure of sequence from Mycobacterium tuberculosis with K, TS1, TS0, D1D and ACY as ligands. Active as Riboflavin synthase, with EC number 2.5.1.9 Known structural/functional Site: . Full crystallographic information is available from OCA.

Reference

Crystal structure of lumazine synthase from Mycobacterium tuberculosis as a target for rational drug design: binding mode of a new class of purinetrione inhibitors., Morgunova E, Meining W, Illarionov B, Haase I, Jin G, Bacher A, Cushman M, Fischer M, Ladenstein R, Biochemistry. 2005 Mar 1;44(8):2746-58. PMID:15723519

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