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Instruments / Technical Area	Publication Details	Published
Krios I-Titan Krios I at Diamond	Plant-made polio type 3 stabilized VLPs—a candidate synthetic polio vaccine Johanna Marsian , Helen Fox , Mohammad W. Bahar , Abhay Kotecha , Elizabeth E. Fry , David I. Stuart , Andrew J. Macadam , David J. Rowlands , George P. Lomonossoff Nature Communications 8 DOI: 10.1038/s41467-017-00090-w Open Access Show Abstract ▼ Abstract: Poliovirus (PV) is the causative agent of poliomyelitis, a crippling human disease known since antiquity. PV occurs in two distinct antigenic forms, D and C, of which only the D form elicits a robust neutralizing response. Developing a synthetically produced stabilized virus-like particle (sVLP)-based vaccine with D antigenicity, without the drawbacks of current vaccines, will be a major step towards the final eradication of poliovirus. Such a sVLP would retain the native antigenic conformation and the repetitive structure of the original virus particle, but lack infectious genomic material. In this study, we report the production of synthetically stabilized PV VLPs in plants. Mice carrying the gene for the human PV receptor are protected from wild-type PV when immunized with the plant-made PV sVLPs. Structural analysis of the stabilized mutant at 3.6 Å resolution by cryo-electron microscopy and single-particle reconstruction reveals a structure almost indistinguishable from wild-type PV3.	Aug 2017
I04-1-Macromolecular Crystallography (fixed wavelength)	Structure of a VP1-VP3 Complex Suggests How Birnaviruses Package the VP1 Polymerase Mohammad Bahar , L. P. Sarin , S. C. Graham , J. Pang , D. H. Bamford , Dave Stuart , Jonathan Grimes Journal of Virology 87 (6), 3229 - 3236 DOI: 10.1128/JVI.02939-12 PMID: 23283942 Diamond Proposal Number(s): [8423] Show Abstract ▼ Abstract: Infectious pancreatic necrosis virus (IPNV), a member of the family Birnaviridae, infects young salmon, with a severe impact on the commercial sea farming industry. Of the five mature proteins encoded by the IPNV genome, the multifunctional VP3 has an essential role in morphogenesis; interacting with the capsid protein VP2, the viral double-stranded RNA (dsRNA) genome and the RNA-dependent RNA polymerase VP1. Here we investigate one of these VP3 functions and present the crystal structure of the C-terminal 12 residues of VP3 bound to the VP1 polymerase. This interaction, visualized for the first time, reveals the precise molecular determinants used by VP3 to bind the polymerase. Competition binding studies confirm that this region of VP3 is necessary and sufficient for VP1 binding, while biochemical experiments show that VP3 attachment has no effect on polymerase activity. These results indicate how VP3 recruits the polymerase into birnavirus capsids during morphogenesis.	Feb 2013
	Modulation of apoptosis and pro-inflammatory signalling by vaccinia virus protein N1 Maluquer De Motes , Samantha Cooray , Ren Hongwei , Gabriel M F Almeida , Keiran Mcgourty , Mohammad Bahar , Dave Stuart , Jonathan Grimes , Stephen Graham , Geoffrey Smith Cytokine 56 (1), 109-109 9th Joint Meeting of the International-Cytokine-Society/International-Society-for-Interferon-and- Cytokine-Research DOI: 10.1016/j.cyto.2011.07.424	Oct 2011
	How vaccinia virus has evolved to subvert the host immune response Mohammad Bahar , Stephen Graham , Ron Chen , Samantha Cooray , Geoffrey Smith , Dave Stuart , Jonathan Grimes Journal Of Structural Biology DOI: 10.1016/j.jsb.2011.03.010 PMID: 21419849 Open Access Show Abstract ▼ Abstract: Viruses are obligate intracellular parasites and are some of the most rapidly evolving and diverse pathogens encountered by the host immune system. Large complicated viruses, such as poxviruses, have evolved a plethora of proteins to disrupt host immune signalling, in their battle against immune surveillance. Recent X-ray crystallographic analysis of these viral immunomodulators has helped form an emerging picture of the molecular details of virus-host interactions. In this review we consider some of these immune evasion strategies as they apply to poxviruses, from a structural perspective, with specific examples from the European SPINE2-Complexes initiative. Structures of poxvirus immunomodulators reveal the capacity of viruses to mimic and compete against the host immune system, using a diverse range of structural folds that are unique or acquired from their hosts with both enhanced and unexpectedly divergent functions.	Apr 2011
	Mapping the iκB kinase beta (ikkβ)-binding interface of B14, a vaccinia virus inhibitor of IKKβ-mediated activation of nuclear factor kappa B Camila Benfield , Daniel Mansur , Laura Mccoy , Brian Ferguson , Mohammad Bahar , Asa Oldring , Jonathan Grimes , Dave Stuart , Stephen Graham , Geoffrey Smith Journal Of Structural Biology DOI: 10.1074/jbc.M111.231381 PMID: 21474453 Open Access Show Abstract ▼ Abstract: The IκB kinase (IKK) complex regulates activation of nuclear factor kappa B (NF-κB), a critical transcription factor in mediating inflammatory and immune responses. Not surprisingly, therefore, many viruses seek to inhibit NF-κB activation. The vaccinia virus (VACV) B14 protein contributes to virus virulence by binding to the IKKβ subunit of the IKK complex and preventing NF-κB activation in response to pro-inflammatory stimuli. Previous crystallographic studies showed that the B14 protein has a Bcl-2-like fold and forms homo-dimers in the crystal. However, multi-angle light scattering indicated that B14 is in monomer:dimer equilibrium in solution. This transient self-association suggested that the hydrophobic dimerisation interface of B14 might also mediate its interaction with IKKβ and this was investigated by introducing amino acid substitutions on the dimer interface. One mutant (Y35E) was entirely monomeric but still co-immunoprecipitated with IKKβ and blocked both NF-κB nuclear translocation and NF-κB-dependent gene expression. Therefore, B14 homo-dimerisation is non-essential for binding and inhibition of IKKβ. In contrast, a second monomeric mutant (F130K) neither bound IKKβ nor inhibited NF-κB-dependent gene expression, demonstrating that this residue is required for the B14-IKKβ interaction. Thus the dimerisation and IKKβ-binding interfaces overlap and lie on a surface used for protein:protein interactions in many viral and cellular Bcl-2-like proteins.	Apr 2011
I03-Macromolecular Crystallography	Vaccinia Virus Proteins A52 and B14 Share a Bcl-2 Like Fold but Have Evolved to Inhibit NF-κB rather than Apoptosis Mohammad Bahar , Samantha Cooray , Ron Chen , Daniel Whalen , Nicola Abrescia , David Alderton , Ray Owens , Geoffrey Smith , Stephen Graham , Dave Stuart Plos Pathogens 4 (8) DOI: 10.1371/journal.ppat.1000128 PMID: 18704168 Open Access Show Abstract ▼ Abstract: Vaccinia virus (VACV), the prototype poxvirus, encodes numerous proteins that modulate the host response to infection. Two such proteins, B14 and A52, act inside infected cells to inhibit activation of NF-κB, thereby blocking the production of pro-inflammatory cytokines. We have solved the crystal structures of A52 and B14 at 1.9 Å and 2.7 Å resolution, respectively. Strikingly, both these proteins adopt a Bcl-2–like fold despite sharing no significant sequence similarity with other viral or cellular Bcl-2–like proteins. Unlike cellular and viral Bcl-2–like proteins described previously, A52 and B14 lack a surface groove for binding BH3 peptides from pro-apoptotic Bcl-2–like proteins and they do not modulate apoptosis. Structure-based phylogenetic analysis of 32 cellular and viral Bcl-2–like protein structures reveals that A52 and B14 are more closely related to each other and to VACV N1 and myxoma virus M11 than they are to other viral or cellular Bcl-2–like proteins. This suggests that a progenitor poxvirus acquired a gene encoding a Bcl-2–like protein and, over the course of evolution, gene duplication events have allowed the virus to exploit this Bcl-2 scaffold for interfering with distinct host signalling pathways.	Aug 2008
	Structure and Function of A41, a Vaccinia Virus Chemokine Binding Protein Mohammad Bahar , Julia C. Kenyon , Mike M. Putz , Nicola Abrescia , James Pease , Emma L. Wise , David I. Stuart , Geoffrey Smith , Jonathan Grimes Plos Pathogens 4 (1) DOI: 10.1371/journal.ppat.0040005 PMID: 18208323 Open Access Show Abstract ▼ Abstract: The vaccinia virus (VACV) A41L gene encodes a secreted 30 kDa glycoprotein that is nonessential for virus replication but affects the host response to infection. The A41 protein shares sequence similarity with another VACV protein that binds CC chemokines (called vCKBP, or viral CC chemokine inhibitor, vCCI), and strains of VACV lacking the A41L gene induced stronger CD8þ T-cell responses than control viruses expressing A41. Using surface plasmon resonance, we screened 39 human and murine chemokines and identified CCL21, CCL25, CCL26 and CCL28 as A41 ligands, with Kds of between 8 nM and 118 nM. Nonetheless, A41 was ineffective at inhibiting chemotaxis induced by these chemokines, indicating it did not block the interaction of these chemokines with their receptors. However the interaction of A41 and chemokines was inhibited in a dose-dependent manner by heparin, suggesting that A41 and heparin bind to overlapping sites on these chemokines. To better understand the mechanism of action of A41 its crystal structure was \u02da solved to 1.9 A resolution. The protein has a globular b sandwich structure similar to that of the poxvirus vCCI family of proteins, but there are notable structural differences, particularly in surface loops and electrostatic charge distribution. Structural modelling suggests that the binding paradigm as defined for the vCCI\u2013chemokine interaction is likely to be conserved between A41 and its chemokine partners. Additionally, sequence analysis of chemokines binding to A41 identified a signature for A41 binding. The biological and structural data suggest that A41 functions by forming moderately strong (nM) interactions with certain chemokines, sufficient to interfere with chemokine-glycosaminogly- can interactions at the cell surface (lM\u2013nM) and thereby to destroy the chemokine concentration gradient, but not strong enough to disrupt the (pM) chemokine-chemokine receptor interactions.	Jan 2008

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