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PDBsum entry 3h6r
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Hydrolase/hydrolase inhibitor
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PDB id
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3h6r
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References listed in PDB file
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Key reference
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Title
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Versatile loops in mycocypins inhibit three protease families.
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Authors
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M.Renko,
J.Sabotic,
M.Mihelic,
J.Brzin,
J.Kos,
D.Turk.
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Ref.
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J Biol Chem, 2009,
285,
308-316.
[DOI no: ]
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PubMed id
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Abstract
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Mycocypins, clitocypin and macrocypins are cysteine protease inhibitors isolated
from the mushrooms Clitocybe nebularis and Macrolepiota procera. Lack of
sequence homology to other families of protease inhibitors suggested that
mycocypins inhibit their target cysteine protease by a unique mechanism and that
a novel fold may be found. The crystal structures of the complex of clitocypin
with the papain-like cysteine protease cathepsin V and of macrocypin and
clitocypin alone have revealed yet another motif of binding to papain
like-cysteine proteases, which in a yet unrevealed way, occludes the catalytic
residue. The binding is associated with a peptide-bond flip of glycine that
occurs prior to or concurrently with the inhibitor docking. Mycocypins possess a
beta-trefoil fold, the hallmark of Kunitz type inhibitors. It is a tree-like
structure with 2 loops in the root region, a stem comprising a six-stranded
beta-barrel, and two layers of loops (6+3) in the crown region. The two loops
that bind to cysteine cathepsins belong to the lower layer of the crown loops,
while a single loop from the crown region can inhibit trypsin or asparaginyl
endopeptidase, as demonstrated by site directed mutagenesis. These loops present
a versatile surface with the potential to bind to additional classes of
proteases. When appropriately engineered, they could provide the basis for
possible exploitation in crop protection.
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Figure 2.
Orientation of the Gly-24-Gly-25 peptide bond in the two
clitocypin molecules. The 2F[obs] − F[calc] electron density
map is contoured at 1 σ. The bonds of glycine 24 are shown in
green, whereas the rest of the chain is shown in red for oxygen,
blue for nitrogen, and orange for carbon. The Gly-24–Gly-25
peptide bond is flexible and can exist in either orientation.
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Figure 3.
The cathepsin V-clitocypin complex. A, shown is the view
along the active site cleft. B, shown is the view perpendicular
to the active site cleft. The folds of cathepsin V and
clitocypin are shown in gray and red. The catalytic cysteine is
shown in yellow. Clitocypin binds into the active site of
cathepsin V in the orientation of a fallen tree with the trunk
and roots pointing sideways and up. The wedge shaped structure
fills the active site cleft along its whole length.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2009,
285,
308-316)
copyright 2009.
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