7CXX
Structural insights into novel mechanisms of inhibition of the major b-carbonic anhydrase CafB from the pathogenic fungus Aspergillus fumigatus (disulfide-bonded form)
Summary for 7CXX
| Entry DOI | 10.2210/pdb7cxx/pdb |
| Descriptor | Carbonic anhydrase, ACETATE ION, SULFATE ION, ... (4 entities in total) |
| Functional Keywords | b-class carbonic anhydrase, zinc metalloenzyme, cafb, aspergillus fumigatus, oxidative inhibition, zinc-free inactivation, lyase |
| Biological source | Neosartorya fumigata (strain ATCC MYA-4609 / Af293 / CBS 101355 / FGSC A1100) |
| Total number of polymer chains | 2 |
| Total formula weight | 52395.46 |
| Authors | |
| Primary citation | Kim, S.,Yeon, J.,Sung, J.,Kim, N.J.,Hong, S.,Jin, M.S. Structural insights into novel mechanisms of inhibition of the major beta-carbonic anhydrase CafB from the pathogenic fungus Aspergillus fumigatus. J.Struct.Biol., 213:107700-107700, 2021 Cited by PubMed Abstract: In fungi the β-class of carbonic anhydrases (β-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 β-CAs, CafA and CafB. Recently we reported the biochemical characterization and 1.8 Å 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 β-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. PubMed: 33545350DOI: 10.1016/j.jsb.2021.107700 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2 Å) |
Structure validation
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