2W3Q

Structure and inhibition of the CO2-sensing carbonic anhydrase Can2 from the pathogenic fungus Cryptococcus neoformans

Summary for 2W3Q

• Entry DOI: 10.2210/pdb2w3q/pdb
• Related: 2W3N
• Descriptor: CARBONIC ANHYDRASE 2, ZINC ION, CHLORIDE ION, ... (4 entities in total)
• Functional Keywords: beta-class carbonic anhydrase, lyase, inhibition, sulfonamide, cryptococcus neoformans
• Biological source: CRYPTOCOCCUS NEOFORMANS
• Total number of polymer chains: 1
• Total formula weight: 27086.45

Authors

Schlicker, C.,Hall, R.A.,Vullo, D.,Middelhaufe, S.,Gertz, M.,Supuran, C.T.,Muehlschlegel, F.A.,Steegborn, C. (deposition date: 2008-11-14, release date: 2008-12-30, Last modification date: 2023-12-13)

Primary citation

Schlicker, C.,Hall, R.A.,Vullo, D.,Middelhaufe, S.,Gertz, M.,Supuran, C.T.,Muehlschlegel, F.A.,Steegborn, C.
Structure and Inhibition of the Co(2)-Sensing Carbonic Anhydrase Can2 from the Pathogenic Fungus Cryptococcus Neoformans.
J.Mol.Biol., 385:1207-, 2009

PubMed 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.

PubMed: 19071134
DOI: 10.1016/J.JMB.2008.11.037

Experimental method

X-RAY DIFFRACTION (1.34 Å)