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PDBsum entry 4inh
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Hydrolase/hydrolase inhibitor
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PDB id
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4inh
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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 basis of substrate specificity and protease inhibition in norwalk virus.
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Authors
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Z.Muhaxhiri,
L.Deng,
S.Shanker,
B.Sankaran,
M.K.Estes,
T.Palzkill,
Y.Song,
B.V.Prasad.
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Ref.
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J Virol, 2013,
87,
4281-4292.
[DOI no: ]
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PubMed id
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Abstract
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Norwalk virus (NV), the prototype human calicivirus, is the leading cause of
nonbacterial acute gastroenteritis. The NV protease cleaves the polyprotein
encoded by open reading frame 1 of the viral genome at five nonhomologous sites,
releasing six nonstructural proteins that are essential for viral replication.
The structural details of how NV protease recognizes multiple substrates are
unclear. In our X-ray structure of an NV protease construct, we observed that
the C-terminal tail, representing the native substrate positions P5 to P1, is
inserted into the active site cleft of the neighboring protease molecule,
providing atomic details of how NV protease recognizes a substrate. The
crystallographic structure of NV protease with the C-terminal tail redesigned to
mimic P4 to P1 of another substrate site provided further structural details on
how the active site accommodates sequence variations in the substrates. Based on
these structural analyses, substrate-based aldehyde inhibitors were synthesized
and screened for inhibition potency. Crystallographic structures of the protease
in complex with each of the three most potent inhibitors were determined. These
structures showed concerted conformational changes in the S4 and S2 pockets of
the protease to accommodate variations in the P4 and P2 residues of the
substrate/inhibitor, which could be a mechanism for how the NV protease
recognizes multiple sites in the polyprotein with differential affinities during
virus replication. These structures further indicate that the mechanism of
inhibition by these inhibitors involves covalent bond formation with the side
chain of the conserved cysteine in the active site by nucleophilic addition, and
such substrate-based aldehydes could be effective protease inhibitors.
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