7cxx

Structural insights into novel mechanisms of inhibition of the major b-carbonic anhydrase CafB from the pathogenic fungus Aspergillus fumigatus (disulfide-bonded form)

spinqualitylabelsall models 7cxx, resolution 2.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2Å Ligands: ACT, SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed In fungi the beta-class of carbonic anhydrases (beta-CAs) are zinc metalloenzymes that are essential for growth, survival, differentiation, and virulence. Aspergillus fumigatus is the most important pathogen responsible for invasive aspergillosis and possesses two major beta-CAs, CafA and CafB. Recently we reported the biochemical characterization and 1.8 A crystal structure of CafA. Here, we report a crystallographic analysis of CafB revealing the mechanism of enzyme catalysis and establish the relationship of this enzyme to other beta-CAs. While CafA has a typical open conformation, CafB, when exposed to acidic pH and/or an oxidative environment, has a novel type of active site in which a disulfide bond is formed between two zinc-ligating cysteines, expelling the zinc ion and stabilizing the inactive form of the enzyme. Based on the structural data, we generated an oxidation-resistant mutant (Y159A) of CafB. The crystal structure of the mutant under reducing conditions retains a catalytic zinc at the expected position, tetrahedrally coordinated by three residues (C57, H113 and C116) and an aspartic acid (D59), and replacing the zinc-bound water molecule in the closed form. Furthermore, the active site of CafB crystals grown under zinc-limiting conditions has a novel conformation in which the solvent-exposed catalytic cysteine (C116) is flipped out of the metal coordination sphere, facilitating release of the zinc ion. Taken together, our results suggest that A. fumigatus use sophisticated activity-inhibiting strategies to enhance its survival during infection. Structural insights into novel mechanisms of inhibition of the major beta-carbonic anhydrase CafB from the pathogenic fungus Aspergillus fumigatus.,Kim S, Yeon J, Sung J, Kim NJ, Hong S, Jin MS J Struct Biol. 2021 Mar;213(1):107700. doi: 10.1016/j.jsb.2021.107700. Epub 2021 , Feb 3. PMID:33545350 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Carbonic anhydrase 3D structures

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