|
|
|
|
|
 |
Contents |
 |
|
|
|
|
|
|
|
|
|
|
|
285 a.a.
|
|
|
|
|
|
|
|
|
|
|
252 a.a.
|
|
|
|
|
|
|
|
|
|
|
238 a.a.
|
|
|
|
|
|
|
|
|
|
|
29 a.a.
|
|
|
|
|
|
|
|
|
|
|
|
|
* Residue conservation analysis
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
The refined structure of human rhinovirus 16 at 2.15 a resolution: implications for the viral life cycle.
|
|
|
Authors
|
|
A.T.Hadfield,
W.Lee,
R.Zhao,
M.A.Oliveira,
I.Minor,
R.R.Rueckert,
M.G.Rossmann.
|
|
|
Ref.
|
|
Structure, 1997,
5,
427-441.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
BACKGROUND: Rhinoviruses belong to the picornavirus family and are small,
icosahedral, non-enveloped viruses containing one positive RNA strand. Human
rhinovirus 16 (HRV16) belongs to the major receptor group of rhinoviruses, for
which the cellular receptor is intercellular adhesion molecule-1 (ICAM-1). In
many rhinoviruses, one of the viral coat proteins (VP1) contains a hydrophobic
pocket which is occupied by a fatty acid-like molecule, or so-called 'pocket
factor'. Antiviral agents have been shown to bind to the hydrophobic pocket in
VP1, replacing the pocket factor. The presence of the antiviral compound blocks
uncoating of the virus and in some cases inhibits receptor attachment. A
refined, high-resolution structure would be expected to provide further
information on the nature of the pocket factor and other features previously not
clearly identified. RESULTS: The structure of native HRV16 has been refined to a
resolution of 2.15 A. The hydrophobic pocket in VP1 is observed in two
alternative conformations. In one of these, the pocket is filled by a pocket
factor and the protein structure is similar to virus-antiviral compound
complexes. In the other conformation, the hydrophobic pocket is collapsed and
empty. RNA bases stack against both a tryptophan and a phenylalanine residue on
the internal surface of the viral capsid. Site-directed mutagenesis of the
tryptophan, which is conserved across the picornaviruses, to nonconservative
residues results in non-viable virus. Five symmetry-related N termini of coat
protein VP4 form a ten-stranded, antiparallel beta barrel around the base of the
icosahedral fivefold axis. The N termini of VP1 are amphipathic alpha helices,
which stack on the outside of this beta barrel. The N termini of VP1 and VP4
have not been observed previously in rhinovirus structures. CONCLUSIONS: The
observation of a partially occupied hydrophobic pocket in HRV16 forms a missing
link between HRV14, which is always observed with no pocket factor in the native
form, and rhinovirus 1A and other picornaviruses (e.g. poliovirus,
coxsackievirus) which contain pocket factors. The pocket factor molecules
probably regulate viral entry, uncoating and assembly. Picornavirus assembly is
known to proceed via pentamers, therefore, the interaction of RNA with the
conserved tryptophan residues across twofold axes between pentamers may play a
role in picornavirus assembly. The positioning of a cation on the icosahedral
fivefold axes and the structure of the N termini of VP4 and VP1 around these
axes suggest a mechanism for the uncoating of rhinoviruses.
|
|
|
|
|
|
Figure 6.
Figure 6. A schematic diagram representing VP1 of HRV16,
showing the binding site of the pocket factor (shown in
ball-and-stick representation) and the WIN antiviral compounds
(shown in pale blue). A cation on the fivefold axis is shown in
yellow. The N termini of VP1, VP3 and VP4 also interact around
the fivefold axis. One copy of each of VP1 and the N termini of
VP3 and VP4 are shown as blue, red and green ribbon diagrams,
respectively. The myristylated N terminus of VP4 is labelled
(MYR). (The diagram was created using MOLSCRIPT [64].)
|
|
|
|
|
|
The above figure is
reprinted
by permission from Cell Press:
Structure
(1997,
5,
427-441)
copyright 1997.
|
|
|
Secondary reference #1
|
|
|
Title
|
|
The structure of human rhinovirus 16.
|
|
|
Authors
|
|
M.A.Oliveira,
R.Zhao,
W.M.Lee,
M.J.Kremer,
I.Minor,
R.R.Rueckert,
G.D.Diana,
D.C.Pevear,
F.J.Dutko,
M.A.Mckinlay.
|
|
|
Ref.
|
|
Structure, 1993,
1,
51-68.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Figure 1.
Fig. 1. Diagrammatic view of picor-
navirus with enlargementofone icosa-
hedral asymmetric unit showing the
outline of the canyon and the entrance
to the WIN pocket. The terms 'north'
(top) and 'south' rims of the canyon
refer to this standard oientation. The
6S protomeric assembly unit (which dif-
fers from the geometric definitionof the
asymmetric unit) is shown in heay out-
line on the icosahedron.
|
|
Figure 4.
Fig. 4. (a) Roadmap showing the amino acids covering the surface of
HRV16. The boundary of the canyon is shown, arbitrar~ily assumed to be
at a plane height of 139A measured along a two-fold axis, as well as
the shaded footprint of the ICAM-1 receptor molecule derived from
cryoelectron microscopy [18]. The footprint was determined as those
residues which have any atom within 4.0 A of any atom of the modeled
receptor molecule. (b) Surface topology of HRV16. Colors represent
relative distances from the viral center in planes perpendicular to a
two-fold axis, with blue being the lowest surface depression and white
the highest surface features. ]Figures computed by the program VSurf
and prepared by JY Sgro, University of Wisconsin, Madison.]
|
|
|
|
|
|
The above figures are
reproduced from the cited reference
with permission from Cell Press
|
|
|
Secondary reference #2
|
|
|
Title
|
|
A comparison of the anti-Rhinoviral drug binding pocket in hrv14 and hrv1a.
|
|
|
Authors
|
|
K.H.Kim,
P.Willingmann,
Z.X.Gong,
M.J.Kremer,
M.S.Chapman,
I.Minor,
M.A.Oliveira,
M.G.Rossmann,
K.Andries,
G.D.Diana.
|
|
|
Ref.
|
|
J Mol Biol, 1993,
230,
206-227.
|
|
|
PubMed id
|
|
|
|
|
|
|
|
|
Secondary reference #3
|
|
|
Title
|
|
Structure of a human rhinovirus complexed with its receptor molecule.
|
|
|
Authors
|
|
N.H.Olson,
P.R.Kolatkar,
M.A.Oliveira,
R.H.Cheng,
J.M.Greve,
A.Mcclelland,
T.S.Baker,
M.G.Rossmann.
|
|
|
Ref.
|
|
Proc Natl Acad Sci U S A, 1993,
90,
507-511.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
|
|
|
Secondary reference #4
|
|
|
Title
|
|
Crystal structure of human rhinovirus serotype 1a (hrv1a).
|
|
|
Authors
|
|
S.S.Kim,
T.J.Smith,
M.S.Chapman,
M.C.Rossmann,
D.C.Pevear,
F.J.Dutko,
P.J.Felock,
G.D.Diana,
M.A.Mckinlay.
|
|
|
Ref.
|
|
J Mol Biol, 1989,
210,
91.
|
|
|
PubMed id
|
|
|
|
|
|
|
|
|
Secondary reference #5
|
|
|
Title
|
|
Common cold viruses
|
|
|
Authors
|
|
M.G.Rossmann,
E.Arnold,
J.P.Griffith,
G.Kamer,
M.Luo,
T.J.Smith,
G.Vriend,
R.R.Rueckert,
B.Sherry,
M.A.Mckinlay,
G.Diana,
M.Otto.
|
|
|
Ref.
|
|
trends biochem sci, 1987,
12,
313.
|
|
|
|
Secondary reference #6
|
|
|
Title
|
|
The site of attachment in human rhinovirus 14 for antiviral agents that inhibit uncoating.
|
|
|
Authors
|
|
T.J.Smith,
M.J.Kremer,
M.Luo,
G.Vriend,
E.Arnold,
G.Kamer,
M.G.Rossmann,
M.A.Mckinlay,
G.D.Diana,
M.J.Otto.
|
|
|
Ref.
|
|
Science, 1986,
233,
1286-1293.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
|
|
|
Secondary reference #7
|
|
|
Title
|
|
Structure of a human common cold virus and functional relationship to other picornaviruses.
|
|
|
Authors
|
|
M.G.Rossmann,
E.Arnold,
J.W.Erickson,
E.A.Frankenberger,
J.P.Griffith,
H.J.Hecht,
J.E.Johnson,
G.Kamer,
M.Luo,
A.G.Mosser.
|
|
|
Ref.
|
|
Nature, 1985,
317,
145-153.
|
|
|
PubMed id
|
|
|
|
|
|
|
|
|
|
|
|
