Crystal structure of thioredoxin 1 from Cryptococcus neoformans at 1.8 Å resolution shows unexpected plasticity of the loop preceding the catalytic site.

An elevated prevalence of cryptococcal infection is a tendency in low-income countries and constitutes a global public health problem due to factors such as the limited efficacy of antifungal therapy and the AIDS/transplant immunocompromised patients. The fungus Cryptococcus neoformans, implicated in this burden, has had several genes validated as drug targets. Among them, the thioredoxin system is one of the major regulators of redox homeostasis and antioxidant defense acting on protein disulfide bonds. Thioredoxin 1 from C. neoformans (CnTrx1) was cloned and expressed in E. coli and the recombinant protein was purified and crystallized. Functional assay shows that CnTrx1 catalyzes the reduction of insulin disulfide bonds using dithiothreitol, while acting as a monomer in solution. The crystal structure of oxidized CnTrx1 at 1.80 Å resolution presents a dimer in the asymmetric unit with typical Trx-fold. Differences between the monomers in the asymmetric unit are found specially in the loop leading to the Cys-Gly-Pro-Cys active-site motif, being even larger when compared to those found between reduced and oxidized states of other thioredoxins. Although the thioredoxins have been isolated and characterized from many organisms, this new structural report provides important clues for understanding the binding and specificity of CnTrx1 to its targets.