1W29

Lumazine Synthase from Mycobacterium tuberculosis bound to 3-(1,3,7- trihydro-9-D-ribityl-2,6,8-purinetrione-7-yl)butane 1-phosphate

Summary for 1W29

• Entry DOI: 10.2210/pdb1w29/pdb
• Related: 1W19
• Descriptor: 6,7-DIMETHYL-8-RIBITYLLUMAZINE SYNTHASE, ACETIC ACID, 4-{2,6,8-TRIOXO-9-[(2R,3S,4R)-2,3,4,5-TETRAHYDROXYPENTYL]-1,2,3,6,8,9-HEXAHYDRO-7H-PURIN-7-YL}BUTYL DIHYDROGEN PHOSPHATE, ... (7 entities in total)
• Functional Keywords: transferase, riboflavin biosynthesis, lumazine synthase, inhibitor binding
• Biological source: MYCOBACTERIUM TUBERCULOSIS
• Total number of polymer chains: 5
• Total formula weight: 85110.14

Authors

Morgunova, E.,Meining, W.,Illarionov, B.,Haase, I.,Fischer, M.,Cushman, M.,Bacher, A.,Ladenstein, R. (deposition date: 2004-07-01, release date: 2005-03-03, Last modification date: 2024-05-08)

Primary citation

Morgunova, E.,Meining, W.,Illarionov, B.,Haase, I.,Jin, G.,Bacher, A.,Cushman, M.,Fischer, M.,Ladenstein, R.
Crystal Structure of Lumazine Synthase from Mycobacterium Tuberculosis as a Target for Rational Drug Design: Binding Mode of a New Class of Purinetrione Inhibitors(,)
Biochemistry, 44:2746-, 2005

PubMed Abstract: 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.

PubMed: 15723519
DOI: 10.1021/BI047848A

Experimental method

X-RAY DIFFRACTION (2.3 Å)