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Dive into the research topics where Rebecca Conners is active.

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Featured researches published by Rebecca Conners.


The EMBO Journal | 2008

The Moraxella adhesin UspA1 binds to its human CEACAM1 receptor by a deformable trimeric coiled‐coil

Rebecca Conners; Darryl J. Hill; Elena Borodina; Christopher Agnew; Sarah J. Daniell; Nicholas Burton; Richard B. Sessions; Anthony R. Clarke; Lucy E. Catto; Donna Lammie; Timothy James Wess; R. Leo Brady; Mumtaz Virji

Moraxella catarrhalis is a ubiquitous human‐specific bacterium commonly associated with upper and lower respiratory tract infections, including otitis media, sinusitis and chronic obstructive pulmonary disease. The bacterium uses an autotransporter protein UspA1 to target an important human cellular receptor carcinoembryonic antigen‐related cell adhesion molecule 1 (CEACAM1). Using X‐ray crystallography, we show that the CEACAM1 receptor‐binding region of UspA1 unusually consists of an extended, rod‐like left‐handed trimeric coiled‐coil. Mutagenesis and binding studies of UspA1 and the N‐domain of CEACAM1 have been used to delineate the interacting surfaces between ligand and receptor and guide assembly of the complex. However, solution scattering, molecular modelling and electron microscopy analyses all indicate that significant bending of the UspA1 coiled‐coil stalk also occurs. This explains how UspA1 can engage CEACAM1 at a site far distant from its head group, permitting closer proximity of the respective cell surfaces during infection.


Journal of Biological Chemistry | 2007

An Unusual Helix-Turn-Helix Protease Inhibitory Motif in a Novel Trypsin Inhibitor from Seeds of Veronica (Veronica hederifolia L.)

Rebecca Conners; Alexander V. Konarev; Jane L. Forsyth; Alison Lovegrove; Justin Marsh; Timothy Joseph-Horne; Peter R. Shewry; R. Leo Brady

The storage tissues of many plants contain protease inhibitors that are believed to play an important role in defending the plant from invasion by pests and pathogens. These proteinaceous inhibitor molecules belong to a number of structurally distinct families. We describe here the isolation, purification, initial inhibitory properties, and three-dimensional structure of a novel trypsin inhibitor from seeds of Veronica hederifolia (VhTI). The VhTI peptide inhibits trypsin with a submicromolar apparent Ki and is expected to be specific for trypsin-like serine proteases. VhTI differs dramatically in structure from all previously described families of trypsin inhibitors, consisting of a helix-turn-helix motif, with the two α helices tightly associated by two disulfide bonds. Unusually, the crystallized complex is in the form of a stabilized acyl-enzyme intermediate with the scissile bond of the VhTI inhibitor cleaved and the resulting N-terminal portion of the inhibitor remaining attached to the trypsin catalytic serine 195 by an ester bond. A synthetic, truncated version of the VhTI peptide has also been produced and co-crystallized with trypsin but, surprisingly, is seen to be uncleaved and consequently forms a noncovalent complex with trypsin. The VhTI peptide shows that effective enzyme inhibitors can be constructed from simple helical motifs and provides a new scaffold on which to base the design of novel serine protease inhibitors.


Journal of Molecular Biology | 2010

Crystal Structure of the LasA Virulence Factor from Pseudomonas aeruginosa: Substrate Specificity and Mechanism of M23 Metallopeptidases

James T. Spencer; Loretta M. Murphy; Rebecca Conners; Richard B. Sessions; Steven J. Gamblin

Pseudomonas aeruginosa is an opportunist Gram-negative bacterial pathogen responsible for a wide range of infections in immunocompromized individuals and is a leading cause of mortality in cystic fibrosis patients. A number of secreted virulence factors, including various proteolytic enzymes, contribute to the establishment and maintenance of Pseudomonas infection. One such is LasA, an M23 metallopeptidase related to autolytic glycylglycine endopeptidases such as Staphylococcus aureus lysostaphin and LytM, and to DD-endopeptidases involved in entry of bacteriophage to host bacteria. LasA is implicated in a range of processes related to Pseudomonas virulence, including stimulating ectodomain shedding of the cell surface heparan sulphate proteoglycan syndecan-1 and elastin degradation in connective tissue. Here we present crystal structures of active LasA as a complex with tartrate and in the uncomplexed form. While the overall fold resembles that of the other M23 family members, the LasA active site is less constricted and utilizes a different set of metal ligands. The active site of uncomplexed LasA contains a five-coordinate zinc ion with trigonal bipyramidal geometry and two metal-bound water molecules. Using these structures as a starting point, we propose a model for substrate binding by LasA that explains its activity against a wider range of substrates than those used by related lytic enzymes, and offer a catalytic mechanism for M23 metallopeptidases consistent with available structural and mutagenesis data. Our results highlight how LasA is a structurally distinct member of this endopeptidase family, consistent with its activity against a wider range of substrates and with its multiple roles in Pseudomonas virulence.


Proceedings of the National Academy of Sciences of the United States of America | 2011

Correlation of in situ mechanosensitive responses of the Moraxella catarrhalis adhesin UspA1 with fibronectin and receptor CEACAM1 binding

Christopher Agnew; Elena Borodina; Nathan R. Zaccai; Rebecca Conners; Nick M Burton; Ja Vicary; D.K Cole; Massimo Antognozzi; Mumtaz Virji; R L Brady

Bacterial cell surfaces are commonly decorated with a layer formed from multiple copies of adhesin proteins whose binding interactions initiate colonization and infection processes. In this study, we investigate the physical deformability of the UspA1 adhesin protein from Moraxella catarrhalis, a causative agent of middle-ear infections in humans. UspA1 binds a range of extracellular proteins including fibronectin, and the epithelial cellular receptor carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1). Electron microscopy indicates that unliganded UspA1 is densely packed at, and extends about 800 Å from, the Moraxella surface. Using a modified atomic force microscope, we show that the adhesive properties and thickness of the UspA1 layer at the cell surface varies on addition of either fibronectin or CEACAM1. This in situ analysis is then correlated with the molecular structure of UspA1. To provide an overall model for UspA1, we have determined crystal structures for two N-terminal fragments which are then combined with a previous structure of the CEACAM1-binding site. We show that the UspA1–fibronectin complex is formed between UspA1 head region and the 13th type-III domain of fibronectin and, using X-ray scattering, that the complex involves an angular association between these two proteins. In combination with a previous study, which showed that the CEACAM1–UspA1 complex is distinctively bent in solution, we correlate these observations on isolated fragments of UspA1 with its in situ response on the cell surface. This study therefore provides a rare direct demonstration of protein conformational change at the cell surface.


Journal of Molecular Biology | 2006

Structural Basis of Substrate Specificity in Human Glyoxylate Reductase/Hydroxypyruvate Reductase

Michael P.S. Booth; Rebecca Conners; Gill Rumsby; R. Leo Brady


Molecular and Biochemical Parasitology | 2005

Mapping the binding site for gossypol-like inhibitors of Plasmodium falciparum lactate dehydrogenase.

Rebecca Conners; F Schambach; Jon Read; Angus Cameron; Richard B. Sessions; Livia Vivas; Anna Easton; Simon L. Croft; R L Brady


Biochemistry | 2005

Structure of Lactate Dehydrogenase from Plasmodium vivax: Complexes with NADH and APADH.

Apirat Chaikuad; Victoria Fairweather; Rebecca Conners; Tim Joseph-Horne; Dilek Turgut-Balik; R. Leo Brady


Biochemistry | 2007

Structural basis for the role of Asp-120 in metallo-beta-lactamases

Jonathan Crisp; Rebecca Conners; James D. Garrity; Anne L. Carenbauer; Michael W. Crowder; James Spencer


Journal of Molecular Biology | 2006

Recognition of oxidatively modified bases within the biotin-binding site of avidin.

Rebecca Conners; E Hooley; Anthony R. Clarke; S Thomas; R.L. Brady


Biophysical Journal | 2011

Multi-Functional Receptor Binding Activity of the Moraxella Catarrhalis Adhesin UspA1

Nathan R. Zaccai; Christopher Agnew; Elena Borodina; Rebecca Conners; Nicholas Burton; David K. Cole; Massimo Antognozzi; Mumtaz Vriji; R. Leo Brady

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