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Schlicker, Christine ; Hall, Rebecca A. ; Vullo, Daniela ; Middelhaufe, Sabine ; Gertz, Melanie ; Supuran, Claudiu T. ; Mühlschlegel, Fritz A. ; Steegborn, Clemens:
Structure and inhibition of the CO₂-sensing carbonic anhydrase Can2 from the pathogenic fungus Cryptococcus neoformans.
In: Journal of Molecular Biology.
Bd. 385
(2009)
Heft 4
.
- S. 1207-1220.
ISSN 0022-2836
DOI: https://doi.org/10.1016/j.jmb.2008.11.037
Abstract
In the pathogenic fungus Cryptococcus neoformans, a CO(2)-sensing system is essential for survival in the natural environment (approximately 0.03% CO(2)) and mediates the switch to virulent growth in the human host (approximately 5% CO(2)). 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.
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| Publikationsform: | Artikel in einer Zeitschrift |
|---|---|
| Begutachteter Beitrag: | Ja |
| Zusätzliche Informationen: | PubMed-ID: 19071134 |
| Institutionen der Universität: | Fakultäten > Fakultät für Biologie, Chemie und Geowissenschaften > Fachgruppe Chemie > Lehrstuhl Biochemie > Lehrstuhl Biochemie I - Proteinbiochemie der Signaltransduktion - Univ.-Prof. Dr. Clemens Steegborn Fakultäten Fakultäten > Fakultät für Biologie, Chemie und Geowissenschaften Fakultäten > Fakultät für Biologie, Chemie und Geowissenschaften > Fachgruppe Chemie Fakultäten > Fakultät für Biologie, Chemie und Geowissenschaften > Fachgruppe Chemie > Lehrstuhl Biochemie |
| Titel an der UBT entstanden: | Nein |
| Themengebiete aus DDC: | 500 Naturwissenschaften und Mathematik > 540 Chemie |
| Eingestellt am: | 16 Apr 2015 12:16 |
| Letzte Änderung: | 11 Jul 2022 13:13 |
| URI: | https://eref.uni-bayreuth.de/id/eprint/10309 |