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PDBsum entry 2bx4
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References listed in PDB file
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Key reference
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Title
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Ph-Dependent conformational flexibility of the sars-Cov main proteinase (m(pro)) dimer: molecular dynamics simulations and multiple x-Ray structure analyses.
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Authors
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J.Tan,
K.H.Verschueren,
K.Anand,
J.Shen,
M.Yang,
Y.Xu,
Z.Rao,
J.Bigalke,
B.Heisen,
J.R.Mesters,
K.Chen,
X.Shen,
H.Jiang,
R.Hilgenfeld.
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Ref.
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J Mol Biol, 2005,
354,
25-40.
[DOI no: ]
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PubMed id
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Abstract
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The SARS coronavirus main proteinase (M(pro)) is a key enzyme in the processing
of the viral polyproteins and thus an attractive target for the discovery of
drugs directed against SARS. The enzyme has been shown by X-ray crystallography
to undergo significant pH-dependent conformational changes. Here, we assess the
conformational flexibility of the M(pro) by analysis of multiple crystal
structures (including two new crystal forms) and by molecular dynamics (MD)
calculations. The MD simulations take into account the different protonation
states of two histidine residues in the substrate-binding site and explain the
pH-activity profile of the enzyme. The low enzymatic activity of the M(pro)
monomer and the need for dimerization are also discussed.
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Figure 1.
Figure 1. Structure of the (a) monomer and (b) dimer of
SARS-CoV Mpro. (a) Domains I (light blue) and II (green) each
contain a six-stranded b-barrel and domain III (orange) is
composed mainly of a-helices. The amino and the carboxy terminus
are marked by a blue and an orange sphere, respectively. The
flexible loops L1, L2, and L3 (red) comprise residues 138-145
(the oxyanion-binding loop), 165-172, and 185-200, respectively.
(b) a-Helices are red and b-strands are light blue. The amino
and the carboxy termini are marked by blue and orange spheres,
respectively. Dimerization is mainly due to interactions between
the helical domains III of each monomer (top). (c)
Superimposition (in stereo) of the C^a backbone as determined in
three different crystal forms. Blue, monoclinic form; red,
tetragonal form; green, orthorhombic form. (a) and (b) were
prepared by MOLSCRIPT,40 (c) was prepared by PyMOL.41
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Figure 8.
Figure 8. Some characteristic distances in the MD
simulations of the SARS-CoV Mpro dimer at (a) pH 6.0, (b) pH
7.6, (c) pH 8.0, and (d) pH 5.0. For each simulation, the
distance between Glu166 and His163, Glu166 and His172, Glu166
and Ser1(N) of the other monomer in the dimer, and Phe140
(center of mass of phenyl ring) and His163 (center of mass of
imidazole ring) are shown. The shorter of the two distances to
the carboxylate oxygen atoms of Glu166, Oe1 and Oe2, is
displayed. Green, monomer A; blue, monomer B.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2005,
354,
25-40)
copyright 2005.
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