 |
PDBsum entry 1zh1
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Metal binding protein
|
PDB id
|
|
|
|
1zh1
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Structure of the zinc-Binding domain of an essential component of the hepatitis c virus replicase.
|
|
|
Authors
|
|
T.L.Tellinghuisen,
J.Marcotrigiano,
C.M.Rice.
|
|
|
Ref.
|
|
Nature, 2005,
435,
374-379.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
Hepatitis C virus (HCV) is a human pathogen affecting nearly 3% of the world's
population. Chronic infections can lead to cirrhosis and liver cancer. The RNA
replication machine of HCV is a multi-subunit membrane-associated complex. The
non-structural protein NS5A is an active component of HCV replicase, as well as
a pivotal regulator of replication and a modulator of cellular processes ranging
from innate immunity to dysregulated cell growth. NS5A is a large phosphoprotein
(56-58 kDa) with an amphipathic alpha-helix at its amino terminus that promotes
membrane association. After this helix region, NS5A is organized into three
domains. The N-terminal domain (domain I) coordinates a single zinc atom per
protein molecule. Mutations disrupting either the membrane anchor or zinc
binding of NS5A are lethal for RNA replication. However, probing the role of
NS5A in replication has been hampered by a lack of structural information about
this multifunctional protein. Here we report the structure of NS5A domain I at
2.5-A resolution, which contains a novel fold, a new zinc-coordination motif and
a disulphide bond. We use molecular surface analysis to suggest the location of
protein-, RNA- and membrane-interaction sites.
|
|
|
|
|
|
|
|
Figure 1.
Figure 1: An overview of the NS5A domain I structure. a,
Schematic of HCV genome organization and the domain structure of
the NS5A protein. The portion of domain I in presented in this
crystal structure is indicated by the red bar. C, capsid
protein; E1 and E2, envelope glycoproteins 1 and 2
(respectively); 4A, NS4A protein. b, Ribbon diagram of the
structure of domain I. The polypeptide chain is coloured from
the N terminus (blue) to C terminus (red). The coordinated zinc
atom is shown in yellow. The C-terminal disulphide bond is shown
in blue. c, A 180° rotation showing the 'back' of domain I. d, A
90° rotation showing the 'top-down' view of domain I. e, Domain
I topology organization model.
|
|
Figure 4.
Figure 4: The NS5A domain I dimer reveals potential interaction
surfaces. a, Ribbon diagrams of three rotations of the domain
I dimer. b, Surface-potential plots of the domain I dimer, with
views corresponding to those shown in a. Analysis of images in a
and b shows that the dimer creates a relatively flat, basic
surface near the N terminus and a large groove between the two
subdomain IB regions. c, Model of NS5A position relative to the
endoplasmic reticulum membrane. The location of the conserved
surface in Fig. 3b is indicated. Helices are from the recent
structure of the NS5A N-terminal helix8.
|
|
|
|
|
|
The above figures are
reprinted
from an Open Access publication published by Macmillan Publishers Ltd:
Nature
(2005,
435,
374-379)
copyright 2005.
|
|
|
|
|
|
|
