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PDBsum entry 1uk4
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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The crystal structures of severe acute respiratory syndrome virus main protease and its complex with an inhibitor.
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Authors
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H.Yang,
M.Yang,
Y.Ding,
Y.Liu,
Z.Lou,
Z.Zhou,
L.Sun,
L.Mo,
S.Ye,
H.Pang,
G.F.Gao,
K.Anand,
M.Bartlam,
R.Hilgenfeld,
Z.Rao.
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Ref.
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Proc Natl Acad Sci U S A, 2003,
100,
13190-13195.
[DOI no: ]
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PubMed id
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Abstract
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A newly identified severe acute respiratory syndrome coronavirus (SARS-CoV), is
the etiological agent responsible for the outbreak of SARS. The SARS-CoV main
protease, which is a 33.8-kDa protease (also called the 3C-like protease), plays
a pivotal role in mediating viral replication and transcription functions
through extensive proteolytic processing of two replicase polyproteins, pp1a
(486 kDa) and pp1ab (790 kDa). Here, we report the crystal structures of the
SARS-CoV main protease at different pH values and in complex with a specific
inhibitor. The protease structure has a fold that can be described as an
augmented serine-protease, but with a Cys-His at the active site. This series of
crystal structures, which is the first, to our knowledge, of any protein from
the SARS virus, reveal substantial pH-dependent conformational changes, and an
unexpected mode of inhibitor binding, providing a structural basis for rational
drug design.
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Figure 1.
Fig. 1. The SARS-CoV Mpro dimer structure complexed with a
substrate-analogue hexapeptidyl CMK inhibitor. (A) The SARS-CoV
Mpro dimer structure is presented as ribbons, and inhibitor
molecules are shown as ball-and-stick models. Protomer A (the
catalytically competent enzyme) is red, protomer B (the inactive
enzyme) is blue, and the inhibitor molecules are yellow. The
N-finger residues of protomer B are green. The molecular surface
of the dimer is superimposed. (B) A cartoon diagram illustrating
the important role of the N-finger in both dimerization and
maintenance of the active form of the enzyme.
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Figure 4.
Fig. 4. Molecular recognition interactions in the
substrate-analogue hexapetidyl CMK inhibitor
(Cbz-Val-Asn-Ser-Thr-Leu-Gln-CMK) complexed with SARS Mpro. (A)
A stereoview of the substrate-binding pocket (green) in protomer
A of the CMK inhibitor complex. The inhibitor molecule (red) is
shown in the 2.5-Å original F[o] - F[c] difference
electron-density map (1.5  ). Hydrogen bonds are
shown as dashed lines. The Gln-P1 is bound to the S1
substrate-specificity subsite, but Leu-P2 fails to bind at the
S2 subsite (near Asp-A187), which is instead occupied by Thr-P3.
The amino acid residues of the protein are labeled in single
letters; for example, H163A stands for His-163 of monomer A
(i.e., His-A163). (B) A stereoview of the substrate-binding
pocket (green) in protomer B of the CMK inhibitor complex. The
inhibitor molecule (red) is shown in the original F[o] - F[c]
difference electron-density map (1.5 ). The Gln-P1 does not
bind to the partly collapsed S1 subsite in this protomer, but
Leu-P2 and Ser-P4 are in their canonical binding sites. See text
for further details.
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