Journal of Structural Biology 175 (2011) 120–126

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Journal of Structural Biology

journal homepage: www.elsevier.com/locate/yjsbi

Review

Cells under siege: Viral glycoprotein interactions at the cell surface

Thomas A. Bowden a,⇑, E. Yvonne Jones a, David I. Stuart a,b
a
Division of Structural Biology, University of Oxford, Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, United Kingdom
b
Science Division, Diamond Light Source Ltd., Diamond House, Harwell Science and Innovation Campus, Didcot, Oxfordshire 0X11 0DE, United Kingdom

a r t i c l e i n f o a b s t r a c t

Article history: As obligate parasites, viruses are required to enter and replicate within their host, a process which
Available online 31 March 2011 employs many of their proteins to hijack natural cellular processes. High resolution X-ray crystallo-
graphic analysis has proven to be an ideal method to visualize the mechanisms by which such virus-host
Keywords: interactions occur and has revealed the innovative capacity of viruses to adapt efficiently to their hosts. In
Glycoprotein structure this review, we draw upon recently elucidated paramyxovirus-, arenavirus-, and poxvirus-host protein
Virus entry complex crystal structures to reveal both the capacity of viruses to appropriate one component of a phys-
Cell signaling
iological protein–protein binding event (often modifying it to out-compete the host-protein), and the
X-ray crystallography
Cell surface receptors
ability to utilize novel binding sites on host cell surface receptors. The structures discussed shed light
on a number of biological processes ranging from viral entry to virulence and host antagonism. Drawn
together they reveal the common strategies which viruses have evolved to interact with their natural
host. The structures also support molecular level rationales for how viruses can be transmitted to unre-
lated organisms and thus pose severe health risks.
Ó 2011 Elsevier Inc. All rights reserved.

1. Introduction Structural investigations of viral attachment glycoproteins, for

Viruses have tremendous genetic diversity (Edwards and Roh-
wer, 2005), a property largely accounted for by rapid replication,
frequent and unspecific mutations arising from error-prone poly-
merases, and an ability to recombine host genes into their own
genome. The resulting capability of a single virion to generate a
genetically diverse complement of progeny provides a simple
mechanism by which virus-host cell interactions can rapidly be-
come specialized for specific host ranges and tissues. Combined
with the ability to ‘steal’ host proteins, this provides a powerful
method by which viruses hijack natural host cell functions, facili-
tating processes such as viral attachment and antagonism of the
host’s innate immune response (Bahar et al., 2011).
Crystallographic studies of viral proteins alone and in complex
with their functional ligands have led to a greater appreciation of
how the structurally dissimilar fold architectures resulting from
viral genomic diversity can achieve analogous biological processes.
Abbreviations: GAP, GTPase-activating protein; IPT, Ig-like plexins and tran-
scription factors; HeV, Hendra virus; HeV-G, Hendra virus attachment glycoprotein;
HNV, Henipavirus; HNV-G, Henipavirus attachment glycoprotein; NiV, Nipah virus;
NiV-G, Nipah virus attachment glycoprotein; MACV, Machupo virus; PDB, protein
databank; PSI, plexin-semaphrorin-integrin domain; r.m.s.d., root mean square
deviation; Tf, transferrin; TfR1, transferrin receptor 1; SLAM, Signaling Lymphocytic
Activation Molecule; SPINE, Structural Proteomics In Europe.
⇑ Corresponding author. Fax: +44 (0)1865 287547.
E-mail address: tom@strubi.ox.ac.uk (T.A. Bowden).
example, have shown that enveloped viruses adopt a wide range
of folds optimized for engagement of their cognate cellular recep-
tors. These folds vary from the compact and novel a/b fold of
Arenaviridae (Fig. 1A) (Abraham et al., 2010; Bowden et al.,
2009a), to the trimeric GP1 ‘chalice’ of the Filoviridae (Fig. 1B)
(Lee et al., 2008), the globular six-bladed b-propeller of the
Paramyxovirinae (Fig. 1C) (Bowden et al., 2010a), the large trimeric
hemagglutinin of the Orthomyxoviridae (Fig. 1D) (Weis et al., 1988;
Wilson et al., 1981), and the highly glycosylated GP120 trimer of
Lentiviruses in the Retroviridae (Wyatt et al., 1998; Zhu et al.,
2003). It is noteworthy that the associated fusion glycoproteins
from each of the above virus families, in contrast to the attachment
glycoproteins, are similar in architecture and have all been
grouped into the first of the three known structural classes of
fusion proteins (Eschli et al., 2006; Lamb and Jardetzky, 2007;
Lee et al., 2008) (Fig. 1AD). It has been suggested that these
proteins are related (Kadlec et al., 2008).
Fusion and receptor-binding proteins are often synthesized on
the same polypeptide and fold together to form complexes on
the virus surface. As a result, these protein pairs have not evolved
entirely independently. Nevertheless, receptor-binding attachment
glycoproteins display much greater structural diversity than their
fusion glycoprotein counter-parts. This is likely to stem from
whether there is a functional requirement for a given viral protein
to adapt to and interact with its hosts. Viral nucleoproteins and fu-
sion glycoproteins (with the exception of the immunosuppressive

1047-8477/$ - see front matter Ó 2011 Elsevier Inc. All rights reserved.
doi:10.1016/j.jsb.2011.03.016
 T.A. Bowden et al. / Journal of Structural Biology 175 (2011) 120–126 121

Fig. 1. Contrasts in fold conservation between attachment and fusion glycoproteins from negative-sense, single-stranded RNA viruses. Receptor-binding attachment
glycoproteins are shown above and the six-helix bundles from their cognate fusion glycoproteins below from (A) Machupo Arenavirus (PDB identification number 2WFO), (B)
Ebola Filovirus (PDB ID 3CSY and 1EBO), (C) Nipah (above) and Parainfluenza type-III (below) Paramyxoviruses (PDB ID 2VSM and 1ZTM, respectively), and (D) Flu
Orthomyxovirus (PDB ID 3LZG). Note for panel A, there are currently no known crystal structures of arenaviral fusion glycoproteins, in panel B, Ebola GP1 is shown with its
non-covalently associated GP2 subunit (gray cartoon), and in panel D, Flu virus haemagglutinin is shown with the HA1 domain colored as a rainbow and the HA2 domain
colored gray.

segments of some fusion glycoproteins) (Avota et al., 2010; Cianciolo well established viral glycoprotein systems including HIV and
et al., 1985; Kleinerman et al., 1987; Volchkov et al., 2001; Yang Measles virus, we illustrate that viruses not only subvert binding
et al., 2000), interact less-specifically with their host cell and have sites that are used in natural physiological signaling processes,
a relatively self-contained function (e.g. insertion into and merging but can also exploit novel sites on host proteins previously not
of the viral and host envelopes or packaging of genomic material) used as interaction surfaces.
which requires minimal adaption. Certain non-structural proteins
and attachment glycoproteins, on the other hand, are examples of
viral proteins which more often interact specifically with their host 2. Viral semaphorins and immune antagonism
cell and adapt rapidly to cellular host factors.
Using recently elucidated paramyxovirus-, arenavirus-, and Semaphorins comprise a family of cell surface signaling glyco-
poxvirus-host complex crystal structures resulting from the Spine proteins which, through binding to the family of plexin glycopro-
(Structural Proteomics In Europe) 2-Complexes initiative as exam- tein cell surface receptors, activate repulsive guidance pathways
ples (detailed in Table 1), we draw upon this second, adaptive which are fundamental to a number of physiological processes
group of viral proteins to reveal the varied strategies employed including axon guidance, immune regulation and activation, and
by viruses when interacting with their hosts. Setting these results vascular development (Kruger et al., 2005; Suzuki et al., 2007).
in a broader context, through comparison with other structurally There are eight known classes of semaphorins: two found in inver-
tebrates, five in vertebrates, and the eighth class in viruses which
are known as ‘viral semaphorins’ (Comeau et al., 1998; Ensser
Table 1 and Fleckenstein, 1995). Whilst the ectodomains of cellular sem-
Relevant structures solved under the European Spine initiatives. aphorins contain C-terminal domain elaborations such as PSI
Structure Reference PDB accession code
(plexin, semaphorin and integrin) domains, immunoglobulin (Ig)-
a
like domains, thrombospondin domains and PDZ-domain-binding
Semaphorin4DEcto Love et al. (2003) 1OLZ
PlexinA2D1-4b Janssen et al. (2010) 3OKT
sites which may or may not attach to the cell-surface, the
Semaphorin6AEcto Janssen et al. (2010) 3OKW N-terminal portion, comprising a plexin-binding sema-domain, is
Semaphorin4DEcto-PlexinB1D1-2 Janssen et al. (2010) 3OL2 well conserved. The sema-domain is the only component found
Semaphorin6AEcto-PlexinA2D1-4 Janssen et al. (2010) 3OKY in viruses. Crystallographic studies, by ourselves and others, have
EphA4LBDc Bowden et al. (2009b) 2WO1
shown that the human Sema3A and mouse Sema4D semadomains
EphA4LBD-ephrinB2RBDd Bowden et al. (2009b) 2WO2
EphA4LBD-ephrinA2RBD Bowden et al. (2009b) 2WO3 consist of a structurally conserved homodimer of seven-bladed
EphA2Ecto Seiradake et al. (2010) 2X10 b-propellers (1.7 Å root mean square deviation, r.m.s.d., for match-
EphA2Ecto-ephrinA5RBD Seiradake et al. (2010) 2X11 ing Ca atoms) (Antipenko et al., 2003; Janssen et al., 2010; Liu
NiV-G Bowden et al. (2008b) 2VWD et al., 2010; Love et al., 2003; Nogi et al., 2010).
HeV-G Bowden et al. (2010b) 2X9M
NiV-G-ephrinB2 Bowden et al. (2008a) 2VSM
The domain architecture is conserved amongst the four classes
HeV-G-ephrinB2 Bowden et al. (2008a) 2VSK (A–D) of vertebrate plexin type-I membrane glycoproteins and
MACV-GP1 Bowden et al. (2009a) 2WFO consists of an N-terminal, membrane distal sema-domain which
a is anchored to the membrane by PSI domains and IPT (Ig-like, plex-
Ecto, entire ectodomain.
b
D1–4, domains 1–4. ins and transcription factors) domains (Bork et al., 1999). A
c
LBD, ligand binding domain. GTPase-binding domain and a C-terminal segment GAP (GTPase-
d
RBD, receptor binding domain. activating protein) domain constitute the intracellular portion of
122 T.A. Bowden et al. / Journal of Structural Biology 175 (2011) 120–126
the glycoprotein and are responsible for activation of Rho family
GTPase signaling pathways within the plexin-expressing cell (Kru-
ger et al., 2005).
Immunoregulatory semaphorins including Sema3A, 4A, 4D, and
7A contribute to B cell mediated immunity (Sema4D), T cell activa-
tion and differentiation (Sema4A, Sema3A, and Sema4D), and
inflammation (Sema7A) (Suzuki et al., 2008). Genomic sequencing
of eukaryotic viruses has revealed that Poxviruses (e.g. Smallpox
virus and Vaccinia virus) and alcelaphine herpes virus encode viral
semaphorins which have been shown to modulate these processes
(Comeau et al., 1998; Ensser and Fleckenstein, 1995; Suzuki et al.,
2008). These viral encoded proteins were presumably ‘stolen’ from
their host during the process of virus-host co-evolution (Suzuki
et al., 2008). The glycoprotein A39R, encoded by Vaccinia virus,
for example, shares highest sequence homology with Sema7A
(30%) and undermines the host immune response by binding to
plexinC1 (Comeau et al., 1998).
Recent crystallographic studies of semaphorin-plexin signaling
complexes, in part within the activity of Spine2-Complexes, have
enabled a detailed comparison of the mechanism by which
natural- and viral-semaphorins bind to plexins. Structures of
Sema7A-plexinC1 (Liu et al., 2010), Sema6A-plexinA2 (Janssen
et al., 2010; Nogi et al., 2010), and Sema4D-plexinB1(Janssen
et al., 2010), have revealed structurally similar signaling com-
plexes, all composed of a Sema-plexin heterotetramer where each
protomer of the semaphorin dimer binds to one plexin seven-
bladed b-propeller sema domain (Fig. 2A and B). Elucidation of
the crystal structure of vaccinia virus A39R in complex with plex-
inC1 demonstrates that poxviruses take advantage of an almost
identical binding mechanism to that of physiological semaphorin-
plexin signaling, where both the viral and the cell semaphorin
b-propellers bind to their cognate plexin b-propellers in a side-on
orientation (Fig. 2C) (Liu et al., 2010). Furthermore, although the
binding interface of the viral complex is less extensive to that
observed in analogous physiological complexes (Sema7A-plex-
inC1), the binding strength of the A39R-plexinC1 interaction is
significantly enhanced (Kd of 10 nM versus 300 nM) (Liu
et al., 2010). Whilst Sema-plexin binding affinities are delicately
balanced to contribute to the complex interplay of interactions
required for physiological functions, Vaccinia virus protein A39R
can simply optimize a single interaction. These studies are an
example of how genetic variability can give rise to mechanisms
which enhance virus virulence and replication. In addition to incor-
porating genes from their host organism, these structures provide a
molecular basis for how viruses can optimize their own proteins to
override normal physiological interactions.
Fig. 2. Poxviral appropriation of semaphorin-plexin interactions. (A) Crystal structure of Sema7a in complex with PlexinC1 (PDB ID 3NVQ). The PlexinC1 seven-bladed b-
propeller domains are rendered as gray surfaces and the Sema7A dimer is shown as a cartoon with each protomer colored as a rainbow with the N-terminus in blue and the C-
terminus in red. Close-up view of protein-protein interactions in the (B) Sema7a-PlexinC1 and (C) poxvirus A39R-PlexinC1 complex (PDB ID 3NVN) interfaces reveal nearly
identical binding modes (colored as in panel A).
3. Henipavirus entry: The ephrin gateway
Nipah virus and Hendra virus compose the genus Henipavirus
within the Paramyxoviridae family and are emergent and highly
virulent bat-borne pathogens found in Africa, Australia, and South
East Asia (Eaton et al., 2006; Wild, 2009). Oligomeric complexes of
two glycoproteins extending outward from the viral envelope are
required for efficient attachment (G glycoprotein) and fusion (F
glycoprotein) into their respective host cells. During henipaviral
attachment, the F glycoprotein is activated in a pH independent
mechanism (Aguilar et al., 2009) to undergo classical class I fusion
rearrangements which merge the host and viral membranes (Lou
et al., 2006).
NiV-G and HeV-G (collectively referred to as HNV-G) are
type-II transmembrane glycoproteins consisting of an N-terminal
cytoplasmic tail, a short transmembrane region, an ectodomain
stalk region, and a C-terminal receptor binding six-bladed b-pro-
peller domain. HNV-G glycoproteins are important in determin-
ing the broad species and cellular tropism of these viruses as
they have been observed to bind specifically with ephrinB2
and ephrinB3 cell surface receptors at nanomolar affinity (Bona-
parte et al., 2005; Negrete et al., 2005, 2006). The sequences of
ephrinB2 and ephrinB3 are well conserved amongst many verte-
brate species including humans, bats, horses, and pigs (>95% se-
quence identity) (Bossart et al., 2008), and they are ubiquitously
expressed in most human tissues due to their importance in fun-
damental bi-directional cell signaling processes such as osteo-
genesis, axon guidance, and vascular development (Hafner
et al., 2004; Pasquale, 2005).
Crystal structures of ephrin ligands alone and in complex with
their Eph receptors (determined by others and as part of Spine2-
Complexes) have been invaluable for identifying the molecular
specificity which underlies normal physiological signaling events.
These studies reveal that the ephrin ectodomain forms a compact
greek-key fold containing a 10 amino acid (GH) binding loop,
which is predominantly responsible for Eph receptor binding
through its insertion into the receptor binding cleft of the mem-
brane-distal Eph receptor b-sandwich domain (Bowden et al.,
2009b; Chrencik et al., 2006a, 2006b; Himanen et al., 2001, 2009,
2010, 2004; Nikolov et al., 2007, 2005; Qin et al., 2010; Seiradake
et al., 2010; Toth et al., 2001) (Fig. 3A).
Site-directed mutagenesis of ephrinB2 and ephrinB3 confirmed
that HNV-G subverts natural Eph receptor binding by also utilizing
this GH loop during viral attachment (Negrete et al., 2006). How-
ever, rather than completely imitating the exact binding mode ob-
served in physiological Eph-ephrin interactions, structural studies
 T.A. Bowden et al. / Journal of Structural Biology 175 (2011) 120–126 123

Fig. 3. Differential utilization of the GHephrinB2 loop by Eph receptors and Henipaviruses. (A) Crystal structure of EphB2 in complex with ephrinB2 (PDB ID 1KGY). (B) Crystal
structure of NiV-G in complex with ephrinB2 (PDB ID 2VSM). For both panels, structures are shown as cartoons with EphB2 and NiV-G colored in gray and ephrinB2 colored as
a rainbow with the N-terminus in blue and the C-terminus in red. The primary ephrinB2 interaction loop is highlighted with a thicker radius and the side-chains of residues
important for both protein-protein interactions are labeled and shown in a ball and stick representation.

of HNV-G alone and in complex with ephrinB2 and ephrinB3 show
that the GH loop is plastic and undergoes a unique rearrangement
that allows it to bind to the top center portion of the HNV-G b-pro-
peller (Fig. 3B) (Bowden et al., 2008a; Xu et al., 2008). As the GH
loop is well conserved between many vertebrate species including
bats and humans, this observation provides a molecular level
rationale for Henipaviral zoonosis (Bowden et al., 2008a). The
conformational changes observed in the ephrins, in addition to
those occurring to the HNV-G b-propeller upon binding (Bowden
et al., 2010b, 2008a, 2008b; Xu et al., 2008), result in a protein-
protein interface which is similarly tight (nanomolar affinity) but
more extensive than physiological Eph-ephrin interactions (an
HNV-G-ephrinB2 interface of approximately 2700 Å2 compared to
an average of 2200 Å2 buried surface area for an Eph-ephrin com-
plex). Despite differences in the extent of these interactions, the
protein-protein interfaces in both sets of structures are dominated
by hydrophobic contacts between aromatic sidechains of ephrinB2
and ephrinB3 (e.g. Phe120ephrinB2 and Trp 125ephrinB2) with binding
pockets on the physiological Eph and viral HNV-G glycoproteins.
Such binding surfaces are reminiscent to the hydrophobic contacts
observed in structures of CD4 in complex with MHC class II and
HIV GP120 glycoproteins. The interfaces in both CD4 complexes
are dominated by the insertion of Phe43CD4 into hydrophobic
cavities present on the MHC and HIV GP120 glycoproteins (Kwong
et al., 1998; Wang et al., 2001).
The structural properties observed in henipavirus-ephrin inter-
actions, in addition to those observed in the attachment glycopro-
teins from other paramyxoviruses (e.g. Measles hemagglutinin in
complex with cell surface SLAM (Hashiguchi et al., 2011) and
CD46 (Santiago et al., 2010)), underscore the adaptability of the
viral six-bladed b-propeller scaffold (Bowden et al., 2010a; Stehle
and Casasnovas, 2009), and in a broader context, the innovative
ability of viruses to alter their glycoprotein repertoire to target
new receptors and hosts.
4. Convergent viral attachment through transferrin receptor
targeting
The transferrin receptor (TfR1) is a type-2 membrane glycopro-
tein which regulates the cellular uptake of iron through binding to
its ligand, transferrin (Tf) and is almost ubiquitously expressed in
different human tissues (Ponka and Lok, 1999). Upon binding to
mono-ferric or di-ferric Tf, the TfR1-Tf complex is internalized
through clathrin-dependent endocytosis and later is freed from
TfR1 in acidic compartments (Ponka and Lok, 1999). TfR1 exists
as a disulfide-linked dimer which consists of an N-terminal cyto-
plasmic domain, a transmembrane region and a 650 amino acid
ectodomain. A major portion of the TfR1 ectodomain has been
crystallized and shown to consist of a protease-like domain, a heli-
cal domain and an apical domain (Fig. 4A) (Bennett et al., 2000;
Lawrence et al., 1999). Structures of TfR1 in complex with Tf and
HFE, a membrane glycoprotein associated with hereditary haemo-
chromatosis (Bomford, 2002; Lebron et al., 1999), have been eluci-
dated by cryo-electron microscopy (Cheng et al., 2004) and
crystallography (Bennett et al., 2000), respectively. HFE can com-
pete with Tf for binding and both complex structures revealed a
2:2 stoichiometry (Fig. 4B). In these structures, the Tf and HFE
binding sites overlap at the membrane proximal TfR1 helical do-
main (Fig. 4B) and are extensive; the crystal structure of the
TfR1–HFE complex revealed the occlusion of approximately
2000 Å2 of solvent accessible surface.
In addition to its importance in iron delivery into cells, TfR1 has
emerged as an entry receptor for a number of important pathogens
including mouse mammary tumor virus (Ross et al., 2002), canine
and panleukopenia feline parvoviruses (Parker et al., 2001), and
New World hemorrhagic fever arenaviruses (Radoshitzky et al.,
2007). These viruses differ markedly in properties: canine and pan-
leukopenia feline parvoviruses are small (26 nm in diameter),
icosohedral, single-stranded DNA viruses that do not contain a
124 T.A. Bowden et al. / Journal of Structural Biology 175 (2011) 120–126

Fig. 4. Contrasting modes of TfR1-host and-virus interactions. (A) Crystal structure of the unbound TfR1ectodomain (PDB ID 1CX8). One TfR1 protomer of the dimer is colored
with the helical domain in blue, the protease-like domain orange, and the apical domain green. (B) Crystal structure of hereditary haemochromatosis protein HFE in complex
with human TfR1 (PDB ID 1DE4). HFE molecules are rendered as gray surfaces and bind to helical TfR1 domains with a 2:2 stoichiometry. TfR1 is rotated by 90° along the
vertical axis with respect to panel A. (C) Crystal structure of Machupo virus attachment glycoprotein GP1 (MACV GP1) in complex with human TfR1 (PDB ID 3KAS). MACV GP1
molecules are rendered as gray surfaces and bind to apical TfR1 domains in a 2:2 stoichiometry. TfR1 is shown in the same orientation as in panel A.

lipid bilayer envelope, whilst mouse mammary tumor virus and
New World hemorrhagic fever arenaviruses are large, plieomor-
phic, enveloped viruses (100 and 120 nm in diameter, respec-
tively) which contain single-stranded RNA genomes. Structural
and functional studies of these viruses have shown that they attach
to sites on TfR1 which do not overlap with the physiological Tf and
HFE binding sites (Radoshitzky et al., 2007). The structure of the
Machupo virus attachment glycoprotein, GP1, determined as a part
of the Spine2-Complexes project, revealed a novel protein fold
(Bowden et al., 2009a). A subsequent crystal structure of GP1 in
complex with TfR1 has revealed an extensive binding site occlud-
ing over 1900 Å2 of solvent accessible surface at the tip of the
membrane distal TfR1 apical domain (Fig. 4C) (Abraham et al.,
2010). Similarly, functional and electron microscopic data suggest
mouse mammary tumor virus and canine and feline parvoviruses
also utilize the TfR1 apical domain for attachment (Goodman
et al., 2010; Hafenstein et al., 2007; Palermo et al., 2003; Wang
et al., 2006).
It has been suggested that this TfR1 ‘viral binding patch’ is used
as it is remote from the known physiological Tf and HFE cellular
binding sites and unlikely to disturb TfR1 endocytosis (Goodman
et al., 2010). Given this hypothesis and the innate ability of viruses
to evolve rapidly, it is not surprising that these diverse viruses have
independently evolved similar molecular mechanisms to rely on
the TfR1 cell surface receptor for virus entry.
5. Concluding remarks
The rapidity of sequence changes in viral genomes is fundamen-
tal for the survival of many viruses. It enables co-evolution with
natural host reservoirs as well as opportunities to adapt to and in-
fect new hosts. Such genetic variability is thus extremely problem-
atic from a biomedical perspective. For example, poxviruses such
as smallpox virus have used these properties to ‘steal’ and optimize
host cell genes such as the plexinC1 interacting semaphorin, A39R,
for antagonism of the host immune system. Emergent RNA viruses
such as henipa- and arena-viruses, on the other hand, have relied
on genetic diversity to develop very different attachment glycopro-
tein folds which can be used to bind to a variety of host cell surface
receptors. The methodological advances in eukaryotic cell expres-
sion for macromolecular crystallography developed in Spine
(Aricescu et al., 2006; Chang et al., 2007) have been invaluable
for understanding the molecular basis of these virus-host cell
interactions.
In this review, recently elucidated virus-host crystal structures,
many of which have emerged from the Spine2-Complexes project,
have shown how viruses both appropriate existing cellular interac-
tions (e.g. A39R binding to PlexinC1 and henipavirus attachment to
ephrins) as well utilize novel modes for host-interaction (e.g. are-
naviral attachment to TfR1). These structural insights when drawn
together reveal common molecular-level strategies which viruses
have evolved to interact with their natural host and result in a dan-
ger to human and animal health.
Acknowledgments
We would like to thank Dr. Richard Elliott, Dr. Max Crispin, and
Dr. Xiaoyun Ji for helpful discussions. David I. Stuart is an Medical
Research Council Professor of Structural Biology, E. Yvonne Jones is
a Cancer Research UK Principal Research Fellow, Thomas A. Bow-
den is a Sir Henry Wellcome Postdoctoral Fellow and Junior Re-
search Fellow at University College, Oxford. This work was
funded by the Wellcome Trust [Grant Number 089026/Z/09/Z],
Medical Research Council, Cancer Research UK, and Spine2-
Complexes [Grant Number FP6-RTD-031220].
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