期刊
JOURNAL OF MOLECULAR BIOLOGY
卷 385, 期 4, 页码 1207-1220出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2008.11.037
关键词
beta-class carbonic anhydrase; Cryptococcus neoformans; crystal structure; inhibition; sulfonamide
资金
- Max-Planck-Institute for Molecular Physiology, Dortmund
- Deutsche Forschungsgemeinschaft [STE1701/2]
- Medical Research Council
- European Union
- Medical Research Council [G0601049] Funding Source: researchfish
- MRC [G0601049] Funding Source: UKRI
In the pathogenic fungus Cryptococcus neoformans, a CO2-sensing system is essential for survival in the natural environment (similar to 0.03% CO2) and mediates the switch to virulent growth in the human host (similar to 5% CO2). This system is composed of the carbonic anhydrase (CA) Can2, which catalyzes formation of bicarbonate, and the fungal, bicarbonate-stimulated adenylyl cyclase Cac1. The critical role of these enzymes for fungal metabolism and pathogenesis identifies them as targets for antifungal drugs. Here, we prove functional similarity of Can2 to the CA Nce103 from Candida albicans and describe its biochemical and structural characterization. The crystal structure of Can2 reveals that the enzyme belongs to the plant-type beta-CAs but carries a unique N-terminal extension that can interact with the active-site entrance of the dimer. We further tested a panel of compounds, identifying nanomolar Can2 inhibitors, and present the structure of a Can2 complex with the inhibitor and product analog acetate, revealing insights into interactions with physiological ligands and inhibitors. (C) 2008 Elsevier Ltd. All rights resented.
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