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PDBsum entry 2zu2
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Hydrolase/hydrolase inhibitor
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PDB id
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2zu2
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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 inhibition specificities of 3c and 3c-Like proteases by zinc-Coordinating and peptidomimetic compounds.
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Authors
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C.C.Lee,
C.J.Kuo,
T.P.Ko,
M.F.Hsu,
Y.C.Tsui,
S.C.Chang,
S.Yang,
S.J.Chen,
H.C.Chen,
M.C.Hsu,
S.R.Shih,
P.H.Liang,
A.H.Wang.
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Ref.
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J Biol Chem, 2009,
284,
7646-7655.
[DOI no: ]
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PubMed id
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Note: In the PDB file this reference is
annotated as "TO BE PUBLISHED". The citation details given above have
been manually determined.
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Abstract
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Human coxsackievirus (CV) belongs to the picornavirus family, which consists of
over 200 medically relevant viruses. In picornavirus, a chymotrypsin-like
protease (3C(pro)) is required for viral replication by processing the
polyproteins, and thus it is regarded as an antiviral drug target. A 3C-like
protease (3CL(pro)) also exists in human coronaviruses (CoV) such as 229E and
the one causing severe acute respiratory syndrome (SARS). To combat SARS, we
previously had developed peptidomimetic and zinc-coordinating inhibitors of
3CL(pro). As shown in the present study, some of these compounds were also found
to be active against 3C(pro) of CV strain B3 (CVB3). Several crystal structures
of 3C(pro) from CVB3 and 3CL(pro) from CoV-229E and SARS-CoV in complex with the
inhibitors were solved. The zinc-coordinating inhibitor is tetrahedrally
coordinated to the His(40)-Cys(147) catalytic dyad of CVB3 3C(pro). The presence
of specific binding pockets for the residues of peptidomimetic inhibitors
explains the binding specificity. Our results provide a structural basis for
inhibitor optimization and development of potential drugs for antiviral
therapies.
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Figure 4.
Peptidomimetic inhibitors bound to the proteases. A, the
active site of CVB3 3C^pro with the bound TG-0204998. Protein is
rendered as a semitransparent solvent-accessible surface with
associated protein backbone and side chain atoms. The oxygen
atoms are shown in red, nitrogen in blue, sulfur in yellow, and
protein carbon atoms in magenta. The inhibitor atoms are shown
as ball-and-stick form and colored in orange for carbon. The
sulfur atom of Cys^147 is covalently attached to the inhibitor
carbon. The substrate binding subsites are designated as S1′,
S1, S2, S3, and S4. B, conserved water molecules, identified by
superimposing the two molecules of CVB3 3C^pro C147A mutant on
the TG-0204998 complex of CVB3 3C^pro. The water molecules are
shown here as spheres colored green/orange (C147A) and magenta
(complex). The protein model of the TG-0204998 complex structure
is shown as an electrostatic surface and TG-0204998 as sticks.
The conserved water molecules of the C147A mutant structure in
the active site are marked. The black star indicates the Michael
addition site. C and D, the active site of SARS 3CL^pro with
bound TG-0204998 (C) and TG-0205486 (D), colored as in A. The
substrate-binding subsites are also indicated.
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Figure 5.
Omit maps of inhibitors. F[o] – F[c] omit maps (magenta)
were calculated for the five inhibitors and contoured at the 2.0
σ level. The inhibitor and inhibitor-binding residues are shown
as ball-and-stick models with carbon atoms in green and gray.
The sulfur, nitrogen, and oxygen atoms are colored in yellow,
blue, and red, respectively. A and B, EPDTC bound to CVB3 3C^pro
and CoV-229E 3CL^pro. The zinc ion (cyan sphere) of EPDTC was
coordinated to the Cys and His residues. C and D, TG-0204998 in
covalent bond with the Cys of CVB3 3C^pro and SARS-CoV 3CL^pro.
E, TG-0205486 in covalent bond with the Cys of SARS-CoV 3CL^pro.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2009,
284,
7646-7655)
copyright 2009.
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