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Instruments / Technical Area	Publication Details	Published
	Signature of antibody domain exchange by native mass spectrometry and collision-induced unfolding Yasunori Watanabe , Snezana Vasiljevic , Joel D. Allen , Gemma E. Seabright , Helen M. E. Duyvesteyn , Katie J. Doores , Max Crispin , Weston B. Struwe Analytical Chemistry DOI: 10.1021/acs.analchem.8b00573 Show Abstract ▼ Abstract: The development of domain-exchanged antibodies offers a route to high-affinity targeting to clustered multivalent epitopes, such as those associated with viral infections and many cancers. One strategy to generate these antibodies is to introduce mutations into target antibodies to drive domain exchange using the only known naturally occurring domain-exchanged anti-HIV (anti-human immunodeficiency virus) IgG1 antibody, 2G12, as a template. Here, we show that domain exchange can be sensitively monitored by ion-mobility mass spectrometry and gas-phase collision-induced unfolding. Using native 2G12 and a mutated form that disrupts domain exchange such that it has a canonical IgG1 architecture (2G12 I19R), we show that the two forms can be readily distinguished by their unfolding profiles. Importantly, the same signature of domain exchange is observed for both intact antibody and isolated Fab fragments. The development of a mass spectrometric method to detect antibody domain exchange will enable rapid screening and selection of candidate antibodies engineered to exhibit this and other unusual quaternary antibody architectures.	May 2018
I02-Macromolecular Crystallography	Convergent immunological solutions to Argentine hemorrhagic fever virus neutralization Antra Zeltina , Stefanie A. Krumm , Mehmet Sahin , Weston B. Struwe , Karl Harlos , Jack H. Nunberg , Max Crispin , Daniel D. Pinschewer , Katie J. Doores , Thomas A. Bowden Proceedings Of The National Academy Of Sciences DOI: 10.1073/pnas.1702127114 Diamond Proposal Number(s): [10627] Show Abstract ▼ Abstract: Transmission of hemorrhagic fever New World arenaviruses from their rodent reservoirs to human populations poses substantial public health and economic dangers. These zoonotic events are enabled by the specific interaction between the New World arenaviral attachment glycoprotein, GP1, and cell surface human transferrin receptor (hTfR1). Here, we present the structural basis for how a mouse-derived neutralizing antibody (nAb), OD01, disrupts this interaction by targeting the receptor-binding surface of the GP1 glycoprotein from Junín virus (JUNV), a hemorrhagic fever arenavirus endemic in central Argentina. Comparison of our structure with that of a previously reported nAb complex (JUNV GP1–GD01) reveals largely overlapping epitopes but highly distinct antibody-binding modes. Despite differences in GP1 recognition, we find that both antibodies present a key tyrosine residue, albeit on different chains, that inserts into a central pocket on JUNV GP1 and effectively mimics the contacts made by the host TfR1. These data provide a molecular-level description of how antibodies derived from different germline origins arrive at equivalent immunological solutions to virus neutralization.	Jun 2017
B21-High Throughput SAXS I04-1-Macromolecular Crystallography (fixed wavelength)	The tetrameric plant lectin BanLec neutralizes HIV through bidentate binding to specific viral glycans Jonathan T. S. Hopper , Stephen Ambrose , Oliver C. Grant , Stefanie A. Krumm , Timothy Allison , Matteo T. Degiacomi , Mark D. Tully , Laura K. Pritchard , Gabriel Ozorowski , Andrew B. Ward , Max Crispin , Katie J. Doores , Robert J. Woods , Justin L. P. Benesch , Carol V. Robinson , Weston B. Struwe Structure DOI: 10.1016/j.str.2017.03.015 Diamond Proposal Number(s): [9384] Show Abstract ▼ Abstract: Select lectins have powerful anti-viral properties that effectively neutralize HIV-1 by targeting the dense glycan shield on the virus. Here, we reveal the mechanism by which one of the most potent lectins, BanLec, achieves its inhibition. We identify that BanLec recognizes a subset of high-mannose glycans via bidentate interactions spanning the two binding sites present on each BanLec monomer that were previously considered separate carbohydrate recognition domains. We show that both sites are required for high-affinity glycan binding and virus neutralization. Unexpectedly we find that BanLec adopts a tetrameric stoichiometry in solution whereby the glycan-binding sites are positioned to optimally target glycosylated viral spikes. The tetrameric architecture, together with bidentate binding to individual glycans, leads to layers of multivalency that drive viral neutralization through enhanced avidity effects. These structural insights will prove useful in engineering successful lectin therapeutics targeting the dense glycan shield of HIV.	Apr 2017
I02-Macromolecular Crystallography I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography	Structures of mammalian ER α-glucosidase II capture the binding modes of broad-spectrum iminosugar antivirals Alessandro T. Caputo , Dominic S. Alonzi , Lucia Marti , Ida-Barbara Reca , John Kiappes , Weston B. Struwe , Alice Cross , Souradeep Basu , Ed Lowe , Benoit Darlot , Angelo Santino , Pietro Roversi , Nicole Zitzmann Proceedings Of The National Academy Of Sciences 113, E4630 - E4638 DOI: 10.1073/pnas.1604463113 Diamond Proposal Number(s): [9306] Show Abstract ▼ Abstract: The biosynthesis of enveloped viruses depends heavily on the host cell endoplasmic reticulum (ER) glycoprotein quality control (QC) machinery. This dependency exceeds the dependency of host glycoproteins, offering a window for the targeting of ERQC for the development of broad-spectrum antivirals. We determined small-angle X-ray scattering (SAXS) and crystal structures of the main ERQC enzyme, ER α-glucosidase II (α-GluII; from mouse), alone and in complex with key ligands of its catalytic cycle and antiviral iminosugars, including two that are in clinical trials for the treatment of dengue fever. The SAXS data capture the enzyme’s quaternary structure and suggest a conformational rearrangement is needed for the simultaneous binding of a monoglucosylated glycan to both subunits. The X-ray structures with key catalytic cycle intermediates highlight that an insertion between the +1 and +2 subsites contributes to the enzyme’s activity and substrate specificity, and reveal that the presence of d-mannose at the +1 subsite renders the acid catalyst less efficient during the cleavage of the monoglucosylated substrate. The complexes with iminosugar antivirals suggest that inhibitors targeting a conserved ring of aromatic residues between the α-GluII +1 and +2 subsites would have increased potency and selectivity, thus providing a template for further rational drug design.	Aug 2016
I02-Macromolecular Crystallography	Studying the active-site loop movement of the São Paolo metallo-β-lactamase-1 Jurgen Brem , Weston B. Struwe , Anna M. Rydzik , Hanna Tarhonskaya , Inga Pfeffer , Emily Flashman , Sander S. Van Berkel , James Spencer , Timothy D. W. Claridge , Michael A. Mcdonough , Justin L. P. Benesch , Christopher J. Schofield Chemical Science 6 (2), 956 - 963 DOI: 10.1039/C4SC01752H PMID: 25717359 Open Access Show Abstract ▼ Abstract: Metallo-β-lactamases (MBLs) catalyse the hydrolysis of almost all β-lactam antibiotics. We report biophysical and kinetic studies on the São Paulo MBL (SPM-1), which reveal its Zn(II) ion usage and mechanism as characteristic of the clinically important di-Zn(II) dependent B1 MBL subfamily. Biophysical analyses employing crystallography, dynamic 19F NMR and ion mobility mass spectrometry, however, reveal that SPM-1 possesses loop and mobile element regions characteristic of the B2 MBLs. These include a mobile α3 region which is important in catalysis and determining inhibitor selectivity. SPM-1 thus appears to be a hybrid B1/B2 MBL. The results have implications for MBL evolution and inhibitor design.	Oct 2014

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