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PDBsum entry 2vbc
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References listed in PDB file
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Key reference
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Title
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Crystal structure of the ns3 protease-Helicase from dengue virus.
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Authors
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D.Luo,
T.Xu,
C.Hunke,
G.Grüber,
S.G.Vasudevan,
J.Lescar.
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Ref.
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J Virol, 2008,
82,
173-183.
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PubMed id
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Abstract
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Several flaviviruses are important human pathogens, including dengue virus, a
disease against which neither a vaccine nor specific antiviral therapies
currently exist. During infection, the flavivirus RNA genome is translated into
a polyprotein, which is cleaved into several components. Nonstructural protein 3
(NS3) carries out enzymatic reactions essential for viral replication, including
proteolysis of the polyprotein through its serine protease N-terminal domain,
with a segment of 40 residues from the NS2B protein acting as a cofactor. The
ATPase/helicase domain is located at the C terminus of NS3. Atomic structures
are available for these domains separately, but a molecular view of the
full-length flavivirus NS3 polypeptide is still lacking. We report a
crystallographic structure of a complete NS3 molecule fused to 18 residues of
the NS2B cofactor at a resolution of 3.15 A. The relative orientation between
the protease and helicase domains is drastically different than the single-chain
NS3-NS4A molecule from hepatitis C virus, which was caught in the act of cis
cleavage at the NS3-NS4A junction. Here, the protease domain sits beneath the
ATP binding site, giving the molecule an elongated shape. The domain arrangement
found in the crystal structure fits nicely into an envelope determined ab initio
using small-angle X-ray scattering experiments in solution, suggesting a stable
molecular conformation. We propose that a basic patch located at the surface of
the protease domain increases the affinity for nucleotides and could also
participate in RNA binding, explaining the higher unwinding activity of the
full-length enzyme compared to that of the isolated helicase domain.
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