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Structure and Inhibition of the CO2-Sensing Carbonic Anhydrase Can2 from the Pathogenic Fungus Cryptococcus neoformans

Schlicker, Christine, Hall, Rebecca A., Vullo, Daniela, Middelhaufe, Sabine, Gertz, Melanie, Supuran, Claudiu T., Mühlschlegel, Fritz A., Steegborn, Clemens (2009) Structure and Inhibition of the CO2-Sensing Carbonic Anhydrase Can2 from the Pathogenic Fungus Cryptococcus neoformans. Journal of Molecular Biology, 385 (4). pp. 1207-1220. ISSN 0022-2836. (doi:10.1016/j.jmb.2008.11.037) (The full text of this publication is not currently available from this repository. You may be able to access a copy if URLs are provided) (KAR id:91848)

The full text of this publication is not currently available from this repository. You may be able to access a copy if URLs are provided.
Official URL
https://doi.org/10.1016/j.jmb.2008.11.037

Abstract

In the pathogenic fungus Cryptococcus neoformans, a CO2-sensing system is essential for survival in the natural environment (∼ 0.03% CO2) and mediates the switch to virulent growth in the human host (∼ 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” β-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.

Item Type: Article
DOI/Identification number: 10.1016/j.jmb.2008.11.037
Divisions: Divisions > Division of Natural Sciences > Biosciences
Depositing User: Becky Hall
Date Deposited: 01 Dec 2021 09:44 UTC
Last Modified: 02 Dec 2021 22:31 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/91848 (The current URI for this page, for reference purposes)
Hall, Rebecca A.: https://orcid.org/0000-0002-4908-8168
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