A5033975156- Protein Structure and Dynamics
- Alzheimer's disease research and treatments
- Enzyme Structure and Function
- Infectious Diseases and Mycology
- Myxozoan Parasites in Aquatic Species
- Phagocytosis and Immune Regulation
- Plant Disease Resistance and Genetics
- Protein purification and stability
- Advanced NMR Techniques and Applications
- Prion Diseases and Protein Misfolding
- Supramolecular Self-Assembly in Materials
- Advanced Synthetic Organic Chemistry
- Viral Infectious Diseases and Gene Expression in Insects
- Monoclonal and Polyclonal Antibodies Research
- Immunotherapy and Immune Responses
- Bacterial Genetics and Biotechnology
- Bioinformatics and Genomic Networks
- Escherichia coli research studies
University of Leeds
2011-2016
Institute of Structural and Molecular Biology
2013
Faculty (United Kingdom)
2013
Abstract Uncontrolled self-association is a major challenge in the exploitation of proteins as therapeutics. Here we describe development structural proteomics approach to identify amino acids responsible for aberrant monoclonal antibodies and design variant with reduced aggregation increased serum persistence vivo. We show that human antibody, MEDI1912, selected against nerve growth factor binds picomolar affinity, but undergoes reversible has poor pharmacokinetic profile both rat...
Amyloid fibrils formed from initially soluble proteins with diverse sequences are associated an array of human diseases. In the disorder, dialysis-related amyloidosis (DRA), contain two major constituents, full-length β2-microglobulin (hβ2m) and a truncation variant, ΔN6 which lacks N-terminal six amino acids. These assembled natively folded all antiparallel β-stranded structure. Here, backbone conformations wild-type hβ2m in their amyloid forms have been determined using combination dilute...
The balance between protein folding and misfolding is a crucial determinant of amyloid assembly. Transient intermediates that are sparsely populated during have been identified as key players in aggregation. However, due to their ephemeral nature, structural characterization these species remains challenging. Here, using the power nonuniformly sampled NMR methods we investigate pathway amyloidogenic nonamyloidogenic variants β2-microglobulin (β2m) atomic detail. Despite via common...
The unfolded ensemble in aqueous solution represents the starting point of protein folding. Characterisation this species is often difficult since native state usually predominantly populated at equilibrium. Previous work has shown that four-helix protein, Im7 (immunity 7), folds via an on-pathway intermediate. While transition states and folding intermediate have been characterised atomistic detail, knowledge under same ambient conditions remained sparse. Here, we introduce destabilising...
Characterising the differences between oligomers formed from amyloidogenic protein β2-microglobulin and its mutant H51A using ESI-IMS-MS.
The mouse and human β2-microglobulin protein orthologs are 70% identical in sequence share 88% similarity. These proteins predicted by various algorithms to have similar aggregation amyloid propensities. However, whilst β2m (hβ2m) forms amyloid-like fibrils denaturing conditions (e.g. pH2.5) the absence of NaCl, (mβ2m) requires addition 0.3M NaCl cause fibrillation. Here, factors which give rise this difference propensity investigated. We utilise structural mutational analyses, fibril growth...