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PDBsum entry 7cxy
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References listed in PDB file
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Key reference
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Title
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Structural insights into novel mechanisms of inhibition of the major β-Carbonic anhydrase cafb from the pathogenic fungus aspergillus fumigatus.
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Authors
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S.Kim,
J.Yeon,
J.Sung,
N.J.Kim,
S.Hong,
M.S.Jin.
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Ref.
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J Struct Biol, 2021,
213,
107700.
[DOI no: ]
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PubMed id
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Abstract
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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.
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