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PDBsum entry 2wct
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RNA binding protein
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PDB id
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2wct
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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 sars-Unique domain (sud) of sars coronavirus contains two macrodomains that bind g-Quadruplexes.
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Authors
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J.Tan,
C.Vonrhein,
O.S.Smart,
G.Bricogne,
M.Bollati,
Y.Kusov,
G.Hansen,
J.R.Mesters,
C.L.Schmidt,
R.Hilgenfeld.
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Ref.
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Plos Pathog, 2009,
5,
e1000428.
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PubMed id
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Abstract
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Since the outbreak of severe acute respiratory syndrome (SARS) in 2003, the
three-dimensional structures of several of the replicase/transcriptase
components of SARS coronavirus (SARS-CoV), the non-structural proteins (Nsps),
have been determined. However, within the large Nsp3 (1922 amino-acid residues),
the structure and function of the so-called SARS-unique domain (SUD) have
remained elusive. SUD occurs only in SARS-CoV and the highly related viruses
found in certain bats, but is absent from all other coronaviruses. Therefore, it
has been speculated that it may be involved in the extreme pathogenicity of
SARS-CoV, compared to other coronaviruses, most of which cause only mild
infections in humans. In order to help elucidate the function of the SUD, we
have determined crystal structures of fragment 389-652 ("SUD(core)") of Nsp3,
which comprises 264 of the 338 residues of the domain. Both the monoclinic and
triclinic crystal forms (2.2 and 2.8 A resolution, respectively) revealed that
SUD(core) forms a homodimer. Each monomer consists of two subdomains, SUD-N and
SUD-M, with a macrodomain fold similar to the SARS-CoV X-domain. However, in
contrast to the latter, SUD fails to bind ADP-ribose, as determined by
zone-interference gel electrophoresis. Instead, the entire SUD(core) as well as
its individual subdomains interact with oligonucleotides known to form
G-quadruplexes. This includes oligodeoxy- as well as oligoribonucleotides.
Mutations of selected lysine residues on the surface of the SUD-N subdomain lead
to reduction of G-quadruplex binding, whereas mutations in the SUD-M subdomain
abolish it. As there is no evidence for Nsp3 entering the nucleus of the host
cell, the SARS-CoV genomic RNA or host-cell mRNA containing long G-stretches may
be targets of SUD. The SARS-CoV genome is devoid of G-stretches longer than 5-6
nucleotides, but more extended G-stretches are found in the 3'-nontranslated
regions of mRNAs coding for certain host-cell proteins involved in apoptosis or
signal transduction, and have been shown to bind to SUD in vitro. Therefore, SUD
may be involved in controlling the host cell's response to the viral infection.
Possible interference with poly(ADP-ribose) polymerase-like domains is also
discussed.
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