A5081507304- Complement system in diseases
- Monoclonal and Polyclonal Antibodies Research
- Erythrocyte Function and Pathophysiology
- Blood groups and transfusion
- Glycosylation and Glycoproteins Research
- Protein Structure and Dynamics
- Blood Coagulation and Thrombosis Mechanisms
- Mosquito-borne diseases and control
- Enzyme Structure and Function
- Renal Diseases and Glomerulopathies
- Platelet Disorders and Treatments
- Retinal Diseases and Treatments
- Toxin Mechanisms and Immunotoxins
- Malaria Research and Control
- HIV Research and Treatment
- Hemoglobin structure and function
- Hemoglobinopathies and Related Disorders
- Historical Art and Culture Studies
- Medical History and Innovations
- Transgenic Plants and Applications
- Herpesvirus Infections and Treatments
- Nanoparticle-Based Drug Delivery
- Proteins in Food Systems
- Galectins and Cancer Biology
- Receptor Mechanisms and Signaling
University of Edinburgh
2015-2024
Northumbria University
1994-2019
Weatherford College
2019
King's College London
2016
Institute of Structural and Molecular Biology
2005-2012
Nirma (India)
2012
Cancer Research UK
2010
Cancer Research UK Manchester Institute
2010
University of Manchester
2010
Radboud University Medical Center
2007
During blood stage Plasmodium falciparum infection, merozoites invade uninfected erythrocytes via a complex, multistep process involving series of distinct receptor-ligand binding events. Understanding each element in this increases the potential to block parasite's life cycle drugs or vaccines. To investigate specific interactions, they were systematically blocked using combination genetic deletion, enzymatic receptor cleavage and inhibition antibodies, peptides small molecules, resulting...
We have used NMR spectroscopy to determine the three-dimensional (3D) structure, and characterize backbone dynamics, of a recombinant version bovine β-lactoglobulin (variant A) at pH 2.6, where protein is monomer. The structure this low-pH form very similar that subunit within dimer 6.2. root-mean-square deviation from 6.2 (crystal) calculated for atoms residues 6−160, ∼1.3 Å. Differences arise orientation, with respect calyx, A−B C−D loops, flanking three-turn α-helix. hydrophobic cavity...
Plasmodium falciparum is responsible for the most severe form of malaria disease in humans, causing more than 1 million deaths each year. As an obligate intracellular parasite, P. falciparum's ability to invade erythrocytes essential its survival within human host. invades using multiple host receptor-parasite ligand interactions known as invasion pathways. Here we show that CR1 erythrocyte receptor PfRh4, a major sialic acid-independent invasion. PfRh4 and interact directly, with K(d) 2.9...
Abstract Human complement factor H, consisting of 20 control protein (CCP) modules, is an abundant plasma glycoprotein. It prevents C3b amplification on self surfaces bearing certain polyanionic carbohydrates, while activation progresses most other, mainly foreign, surfaces. Herein, locations binding sites for polyanions and are reexamined rigorously by overexpressing H segments, structural validation, assays. As anticipated, constructs corresponding to CCPs 7–8 19–20 bind well in...
Nearly 50 million people worldwide suffer from age-related macular degeneration (AMD), which causes severe loss of central vision. A single-nucleotide polymorphism in the gene for complement regulator factor H (FH), a Tyr-to-His substitution at position 402, is linked to ∼50% attributable risks AMD. We present crystal structure region FH containing polymorphic amino acid His402 complex with an analogue glycosaminoglycans (GAGs) that localize on cell surface. The demonstrates direct...
Factor H (fH) is essential for complement homeostasis in fluid-phase and on surfaces. Its two C-terminal domains (CCP 19-20) anchor fH to self-surfaces where it prevents C3b amplification a process requiring its N-terminal four domains. In atypical hemolytic uremic syndrome (aHUS), mutations clustering toward the C terminus of may disrupt interactions with surface-associated or polyanions thereby diminish ability regulate complement. To test this, we compared recombinant protein encompassing...
Therapeutic modulation of the complement system has become increasingly important in line with growing recognition role numerous diseases. Compstatin, a peptidic inhibitor that acts at central level cascade, is currently clinical evaluation but routes to improve its efficacy have not yet been fully explored. Here, we report improvements both inhibitory potency and pharmacokinetic parameters compstatin broaden applications. Selective modification N-terminus non-proteinogenic amino acids...
Inadequate control of the complement system is underlying or aggravating factor in many human diseases. Whereas treatment options that specifically target alternative pathway (AP) activation are considered highly desirable, no such option available clinic. In this study, we present a successful example protein engineering, guided by structural insight on regulator H (FH), yielding novel complement-targeted therapeutic (mini-FH) with clinical potential. Despite 70% reduction size, mini-FH...
Abstract The plasma protein factor H primarily controls the activation of alternative pathway complement. C-terminal is known to be involved in protection host cells from complement attack. In present study, we show that domains 19–20 alone are capable discriminating between host-like and complement-activating cells. Furthermore, although possesses three binding sites for C3b, cell-bound C3b can almost completely inhibited by single site located 19–20. All regulatory activities expressed...
Membrane cofactor protein (MCP; CD46), a widely distributed regulator of complement activation, is for the factor I-mediated degradation C3b and C4b deposited on host cells. MCP possesses four extracellular, contiguous control modules (CCPs) important this inhibitory activity. The goal present study was to delineate functional sites within these modules. We employed multiple approaches including mutagenesis, epitope mapping, comparisons primate make following observations. First, were...
A short stretch of 35 amino acids is identified as the structural motif responsible for tight parallel association and trimerization three identical polypeptide chains lung surfactant protein D, which contains both collagen regions C-type lectin domains. This 'neck-region' located at nucleation site collagenous sequences fold into a staggered triple-helix shown, by CD, NMR, cross-linking recombinant peptides, to consist triple-stranded alpha-helical bundle in non-staggered, extremely strong,...
A common single nucleotide polymorphism in the factor H gene predisposes to age-related macular degeneration. Factor blocks alternative pathway of complement on self-surfaces bearing specific polyanions, including glycosaminoglycan chains proteoglycans. also binds C-reactive protein, potentially contributing noninflammatory apoptotic processes. The at risk sequence contains His (rather than Tyr) position 402 (384 mature protein), seventh 20 control protein (CCP) modules (CCP7) H. We...
The defining activity of the homeodomain protein Nanog is ability to confer cytokine-independent self-renewal upon ES (embryonic stem) cells in which it overexpressed. However, biochemical basis by achieves this function remains unknown. In present study, we show that dimerizes through a functionally critical domain. Co-immunoprecipitation molecules tagged with distinct epitopes demonstrates self-associates region every fifth residue tryptophan. vitro binding experiments establish...