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PDBsum entry 1quv
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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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Crystal structure of the RNA-Dependent RNA polymerase of hepatitis c virus.
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Authors
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H.Ago,
T.Adachi,
A.Yoshida,
M.Yamamoto,
N.Habuka,
K.Yatsunami,
M.Miyano.
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Ref.
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Structure, 1999,
7,
1417-1426.
[DOI no: ]
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PubMed id
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Abstract
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BACKGROUND: Hepatitis C virus (HCV) is the major etiological agent of
hepatocellular carcinoma, and HCV RNA-dependent RNA polymerase (RdRp) is one of
the main potential targets for anti-HCV agents. HCV RdRp performs run-off
copying replication in an RNA-selective manner for the template-primer duplex
and the substrate, but the structural basis of this reaction mechanism has still
to be elucidated. RESULTS: The three-dimensional structure of HCV RdRp was
determined by X-ray crystallography at 2.5 A resolution. The compact HCV RdRp
structure resembles a right hand, but has more complicated fingers and thumb
domains than those of the other known polymerases, with a novel alpha-helix-rich
subdomain (alpha fingers) as an addition to the fingers domain. The other
fingers subdomain (beta fingers) is folded in the same manner as the fingers
domain of human immunodeficiency virus (HIV) reverse transcriptase (RT), another
RNA-dependent polymerase. The ribose-recognition site of HCV RdRp is constructed
of hydrophilic residues, unlike those of DNA polymerases. The C-terminal region
of HCV RdRp occupies the putative RNA-duplex-binding cleft. CONCLUSIONS: The
structural basis of the RNA selectivity of HCV RdRp was elucidated from its
crystal structure. The putative substrate-binding site with a shallow
hydrophilic cavity should have ribonucleoside triphosphate (rNTP) as the
preferred substrate. We propose that the unique alpha fingers might represent a
common structural discriminator of the template-primer duplex that distinguishes
between RNA and DNA during the replication of positive single-stranded RNA by
viral RdRps. The C-terminal region might exert a regulatory function on the
initiation and activity of HCV RdRp.
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Figure 3.
Figure 3. Structure comparison of HCV RdRp with poliovirus
RdRp and HIV RT and with the Mrf-2 DNA-binding domain. (a)
Stereoview of superimposed wire models of the a- and b-fingers
subdomains and palm domain of HCV RdRp and the corresponding
portions of poliovirus RdRp [13] and the ternary complex of HIV
RT [24]. The a fingers, b fingers, and palm of HCV RdRp are
shown in green, cyan, and pink, respectively. Poliovirus RdRp is
shown in silver and HIV RT is shown in gold. The positively
charged residues mentioned in the text are represented by blue
balls and sticks. In the b-fingers subdomain, the basic residues
are Lys51, Arg48, Arg158, Lys155 and Lys141 from the outside. In
the a fingers, the residues are Lys98, Arg168, Lys172, Lys90,
Arg109 and Lys106 from the top right in a clockwise direction.
(b) Stereoview of superimposed wire models of the thumb domains
of HCV RdRp (violet), poliovirus RdRp (silver) [13] and HIV RT
(gold) [24]. (c) Stereoview of superimposed wire models of the
a-fingers region, including its connecting b1-b2 loop in the
b-fingers subdomain (residues 74-189), of HCV RdRp (blue) and
the Mrf-2 DNA-binding domain (red) [25].
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The above figure is
reprinted
by permission from Cell Press:
Structure
(1999,
7,
1417-1426)
copyright 1999.
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