A5091080514- Peptidase Inhibition and Analysis
- Monoclonal and Polyclonal Antibodies Research
- Viral Infections and Immunology Research
- Glycosylation and Glycoproteins Research
- Animal Disease Management and Epidemiology
- Viral Infectious Diseases and Gene Expression in Insects
- Neuropeptides and Animal Physiology
- Biochemical and Structural Characterization
- Viral gastroenteritis research and epidemiology
- Galectins and Cancer Biology
- Animal Virus Infections Studies
- Escherichia coli research studies
- Sleep and Wakefulness Research
- Advanced biosensing and bioanalysis techniques
- Chemical Synthesis and Analysis
- RNA modifications and cancer
- HER2/EGFR in Cancer Research
- Cellular transport and secretion
- Cancer-related gene regulation
- Vector-Borne Animal Diseases
- RNA regulation and disease
- Lung Cancer Research Studies
- Sleep and related disorders
- Lipid Membrane Structure and Behavior
- Barrier Structure and Function Studies
UCB Pharma (United Kingdom)
2020-2021
University of Massachusetts Chan Medical School
2015-2021
University College Birmingham
2020-2021
University of Edinburgh
2015
University of Manchester
2009-2013
National Centre of Scientific Research "Demokritos"
2011-2013
Imperial College London
2002-2013
University of Alberta
2005
Background Anti-human epidermal growth factor receptor 2 (HER2) IgG1-based antibody therapies significantly improve cancer prognosis, yet intrinsic or acquired resistance to fragment antigen-binding (Fab)-mediated direct effects commonly occurs. Most resistant tumors retain antigen expression and therefore remain potentially targetable with anti-HER2 that promote immune-mediated responses. Tumor-antigen-specific IgE class antibodies can mediate powerful immune cell-mediated against different...
Significance Intrinsically disordered proteins lack persistent folded structure but are abundant and critical for regulatory protein interactions. They represent a challenge to the structure/function paradigm, particularly when significant disorder remains on interaction with partners. Although many interactions have been described, little is known about multiple of hub or dependence posttranslational modifications network from biophysical perspective. Cystic fibrosis transmembrane...
Significance The human immune system fights disease by eradicating sick cells after first recognizing that they are infected or cancerous. This is achieved specialized detect on the surface of other small molecules called antigenic peptides. Pathogens and cancer can evade stopping generation We designed, synthesized evaluated artificial effectively block a group enzymes key for production destruction show these compounds enhance peptides in reaction toward cancer. Inhibitors this kind may...
Abstract Background Tumor-targeting IgE antibodies have elicited potent tumor-restricting effects by recruiting immune effector mechanisms. However, a dedicated platform for the generation, selection and evaluation of novel IgEs based on target antigen recognition functional profiles has not been reported. Methods By establishing an class antibody therapeutic design to allow lead candidates, we generated panel recognising human epidermal growth factor receptor 2 (HER2), overexpressed in...
Abstract Endoplasmic reticulum aminopeptidases 1 and 2 (ERAP1 ERAP2) cooperate to trim antigenic peptide precursors for loading onto MHC class I molecules help regulate the adaptive immune response. Common coding single nucleotide polymorphisms in ERAP1 ERAP2 have been linked with predisposition human diseases ranging from viral bacterial infections autoimmunity cancer. It has hypothesized that altered Ag processing by these enzymes is a causal link disease etiology, but molecular mechanisms...
Endoplasmic reticulum aminopeptidases ERAP1 and ERAP2 cooperate to trim a vast variety of antigenic peptide precursors generate mature epitopes for binding major histocompatibility class I molecules. We report here the first structure determined at 3.08 Å by X-ray crystallography. On basis residual electron density, lysine residue has been modeled in active site enzyme; thus, corresponds an enzyme-product complex. The overall domain organization is highly similar that recently its closed...
The 3C protease (3C(pro)) from foot-and-mouth disease virus (FMDV), the causative agent of a widespread and economically devastating domestic livestock, is potential target for antiviral drug design. We have determined structure new crystal form FMDV 3C(pro), chymotrypsin-like cysteine protease, which reveals features that are important catalytic activity. In particular, we show surface loop was disordered in previous structures adopts beta-ribbon conformationally similar to equivalent...
Shigella is unique among enteric pathogens, as it invades colonic epithelia through the basolateral pole. Therefore, has evolved ability to breach intestinal epithelial barrier deploy an arsenal of effector proteins, which permits bacterial invasion and leads a severe inflammatory response. However, mechanisms used by regulate permeability remain unknown. To address this question, we both polarized model human ex-vivo further characterize early events host-bacteria interactions. Our results...
Abstract Individuals with narcolepsy suffer from abnormal sleep patterns due to loss of neurons that uniquely supply hypocretin (HCRT). Previous studies found associations the human leukocyte antigen (HLA)-DQ6 allele and T-cell receptor α (TRA) J24 gene segment also suggested in vitro-stimulated T cells can target HCRT. Here, we present evidence vivo expansion DQ6-HCRT tetramer + /TRAJ24 /CD4 DQ6 individuals without narcolepsy. We identify related TRAJ24 TCRαβ clonotypes encoded by identical...
The uridylylation of the VPg peptide primer is first stage in replication picornavirus RNA. This process can be achieved vitro using purified components, including 3B (VPg) with RNA dependent polymerase (3Dpol), precursor 3CD, and an template containing cre/bus. We show that certain sequences within foot-and-mouth disease virus (FMDV) 5' untranslated region but outside cre/bus enhance activity. Furthermore, we have shown FMDV 3C protein alone substitute for albeit less efficiently. In...
ABSTRACT We report the solution structures of VPg proteins from feline calicivirus (FCV) and murine norovirus (MNV), which have been determined by nuclear magnetic resonance spectroscopy. In both cases, core protein adopts a compact helical structure flanked flexible N C termini. Remarkably, while FCV contains well-defined three-helix bundle, MNV has just first two these secondary elements. cores are stabilized networks hydrophobic salt bridge interactions. The Tyr residue in that is...
Bovines have evolved a subset of antibodies with ultra-long heavy chain complementarity determining regions that harbour cysteine-rich knob domains. To produce high-affinity peptides, we previously isolated autonomous 3–6 kDa domains from bovine antibodies. Here, show binding four domain peptides elicits range effects on the clinically validated drug target complement C5. Allosteric mechanisms predominated, one peptide selectively inhibiting C5 cleavage by alternative pathway convertase,...
IgG-based anti-cancer therapies have achieved promising clinical outcomes, but, especially for patients with solid tumors, response rates vary. IgE antibodies promote distinct immune responses compared to IgG and shown anti-tumoral pre-clinical activity preliminary efficacy safety profile in testing. To improve potency further, we engineered a hybrid IgE-IgG1 antibody (IgEG), combine the functions of both isotypes. Two IgEGs were generated variable regions taken from trastuzumab (Tras IgEG)...
Foot-and-mouth disease virus (FMDV) 3C protease (3C(pro)) plays a vital role in replication by performing most of the cleavages required to divide viral polyprotein precursor into its functional component proteins. To date, no structural information has been available for FMDV 3C(pro), which is an attractive target antiviral drugs. Targeted mutagenesis surface amino acids identified two Cys residues that were detrimental solubility and contributed time-dependent formation proteinaceous skin...
Cysteine-rich knob domains found in the ultralong complementarity determining regions of a subset bovine antibodies are capable functioning autonomously as 3-6 kDa peptides. While they can be expressed recombinantly cellular systems, this paper we show that also readily amenable to chemical synthesis, with co-crystal structure chemically synthesized domain complex an antigen showing structural equivalence biological product. For drug discovery, following immunization cattle, peptides...
Shigella spp. are highly adapted pathogens that cause bacillary dysentery in human and nonhuman primates. An unusual feature of pathogenesis is this organism invades the colonic epithelia from basolateral pole. Therefore, it has evolved ability to disrupt intestinal epithelial barrier reach surface. We have shown previously secreted serine protease A (SepA), which belongs family autotransporters Enterobacteriaceae, responsible for initial destabilization facilitates invasion. However,...
Abstract Mutations in the photoreceptor-specific tetraspanin gene peripherin-2 ( PRPH2 ) lead to widely varying forms of retinal degeneration ranging from retinitis pigmentosa macular dystrophy. Both inter- and intra-familial phenotypic heterogeneity has led much interest uncovering complex pathogenic mechanisms -associated disease. Majority disease-causing mutations reside second intradiscal loop, wherein seven cysteines control protein folding oligomerization. Here, we utilize knockin...
Abstract OPCML , a tumor suppressor gene, is frequently silenced epigenetically in ovarian and other cancers. Here we report, by analysis of databases sequences, the observation somatic missense mutations from various types impact these on function, solving X-ray crystal structure this glycoprotein to 2.65 Å resolution. consists an extended arrangement three immunoglobulin-like domains homodimerizes via network contacts between membrane-distal domains. We report generation panel variants...