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Crystal structure of the ATPase-C domain of the chromatin remodeller Fun30 from Saccharomyces cerevisiae.

ABSTRACT: Fun30 (Function unknown now 30) is a chromatin remodeller belonging to the Snf2 family. It has previously been reported to be a regulator of several cellular activities, including DNA repair, gene silencing and maintenance of chromatin structure. Here, the crystal structure of the Fun30 ATPase-C domain (the C-lobe of the ATPase domain) is reported at 1.95?Å resolution. Although the structure displays overall similarities to those of other Snf2 family members, a new structural module was found to be specific to the Fun30 subfamily. Fun30 ATPase-C was shown be monomeric in solution and showed no detectable affinity for dsDNA.

SUBMITTER: Liu L

PROVIDER: S-EPMC5287370 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Crystal structure of the ATPase-C domain of the chromatin remodeller Fun30 from Saccharomyces cerevisiae.

Liu Lan L Jiang Tao T

Acta crystallographica. Section F, Structural biology communications 20170101 Pt 1

Fun30 (Function unknown now 30) is a chromatin remodeller belonging to the Snf2 family. It has previously been reported to be a regulator of several cellular activities, including DNA repair, gene silencing and maintenance of chromatin structure. Here, the crystal structure of the Fun30 ATPase-C domain (the C-lobe of the ATPase domain) is reported at 1.95 Å resolution. Although the structure displays overall similarities to those of other Snf2 family members, a new structural module was found to ...[more]

PMID: 28045388

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Project description:BackgroundAs the third enzyme of the pentose phosphate pathway, 6-phosphogluconate dehydrogenase (6PGDH) is the main generator of cellular NADPH. Both thioredoxin reductase and glutathione reductase require NADPH as the electron donor to reduce oxidized thioredoxin or glutathione (GSSG). Since thioredoxin and GSH are important antioxidants, it is not surprising that 6PGDH plays a critical role in protecting cells from oxidative stress. Furthermore the activity of 6PGDH is associated with several human disorders including cancer and Alzheimer's disease. The 3D structural investigation would be very valuable in designing small molecules that target this enzyme for potential therapeutic applications.ResultsThe crystal structure of 6-phosphogluconate dehydrogenase (6PGDH/Gnd1) from Saccharomyces cerevisiae has been determined at 2.37 A resolution by molecular replacement. The overall structure of Gnd1 is a homodimer with three domains for each monomer, a Rossmann fold NADP+ binding domain, an all-alpha helical domain contributing the majority to hydrophobic interaction between the two subunits and a small C-terminal domain penetrating the other subunit. In addition, two citrate molecules occupied the 6PG binding pocket of each monomer. The intact Gnd1 had a Km of 50 +/- 9 microM for 6-phosphogluconate and of 35 +/- 6 microM for NADP+ at pH 7.5. But the truncated mutants without the C-terminal 35, 39 or 53 residues of Gnd1 completely lost their 6PGDH activity, despite remaining the homodimer in solution.ConclusionThe overall tertiary structure of Gnd1 is similar to those of 6PGDH from other species. The substrate and coenzyme binding sites are well conserved, either from the primary sequence alignment, or from the 3D structural superposition. Enzymatic activity assays suggest a sequential mechanism of catalysis, which is in agreement with previous studies. The C-terminal domain of Gnd1 functions as a hook to further tighten the dimer, but it is not necessary for the dimerization. This domain also works as a lid on the substrate binding pocket to control the binding of substrate and the release of product, so it is indispensable for the 6PGDH activity. Moreover, the co-crystallized citrate molecules, which mimic the binding mode of the substrate 6-phosphogluconate, provided us a novel strategy to design the 6PDGH inhibitors.

Dataset Information

Crystal structure of the ATPase-C domain of the chromatin remodeller Fun30 from Saccharomyces cerevisiae.

Publications

Crystal structure of the ATPase-C domain of the chromatin remodeller Fun30 from Saccharomyces cerevisiae.

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