A5070062917- Enzyme Structure and Function
- Protein Structure and Dynamics
- Heat shock proteins research
- RNA and protein synthesis mechanisms
- Malaria Research and Control
- Immune Response and Inflammation
- Glycosylation and Glycoproteins Research
- Immune Cell Function and Interaction
- HIV Research and Treatment
- Mosquito-borne diseases and control
- RNA Research and Splicing
- Monoclonal and Polyclonal Antibodies Research
- vaccines and immunoinformatics approaches
- Invertebrate Immune Response Mechanisms
- Enzyme Catalysis and Immobilization
- Diabetes and associated disorders
- Cell Adhesion Molecules Research
- Fungal and yeast genetics research
- Infant Nutrition and Health
- DNA and Nucleic Acid Chemistry
- Trypanosoma species research and implications
- Amino Acid Enzymes and Metabolism
- Cancer, Hypoxia, and Metabolism
- Medical and Biological Ozone Research
- Synthesis and Reactivity of Sulfur-Containing Compounds
Scripps Research Institute
2016-2024
International AIDS Vaccine Initiative
2018-2024
Max Planck Unit for the Science of Pathogens
2021-2022
Lund University
2008-2021
The Plasmodium falciparum Pfs25 protein (Pfs25) is a leading malaria transmission-blocking vaccine antigen. vaccination intended to elicit antibodies that inhibit parasite development when ingested by Anopheles mosquitoes during blood meals. three-dimensional structure has remained elusive, hampering molecular understanding of its function and limiting immunogen design. We report six crystal structures in complex with elicited immunization via virus-like particles human immunoglobulin loci...
The insufficient operational stability of amine transaminases (ATA) constitutes a limiting factor for high productivity in chiral synthesis. In this work, we investigated the tetrameric ATA with 92% sequence identity to Pseudomonas sp. transaminase and compared it two commonly used dimeric ATAs from Chromobacterium violaceum Vibrio fluvialis. presence substrate, all three featured reduced comparison their resting stability, but tetramer showed slower inactivation rates than ATAs. Kinetic...
Germline-targeting (GT) protein immunogens to induce VRC01-class broadly neutralizing antibodies (bnAbs) the CD4-binding site of HIV envelope (Env) have shown promise in clinical trials. Here, we preclinically validated a lipid nanoparticle-encapsulated nucleoside mRNA (mRNA-LNP) encoding eOD-GT8 60mer as soluble self-assembling nanoparticle mouse models. In model with three humanized B cell lineages bearing distinct VRC01-precursor receptors (BCRs) similar affinities for eOD-GT8, all could...
The mucosal immune system identifies and fights invading pathogens, while allowing non-pathogenic organisms to persist. Mechanisms of pathogen/non-pathogen discrimination are poorly understood, as is the contribution human genetic variation in disease susceptibility. We describe here a new, IRF3-dependent signaling pathway that critical for distinguishing pathogens from normal flora at barrier. Following uropathogenic E. coli infection, Irf3(-/-) mice showed pathogen-specific increase acute...
Structure-based protein design offers a possibility of optimizing the overall shape engineered binding scaffolds to match their targets better. We developed computational approach for structure-based repeat proteins that allows adjustment geometrical features like length, curvature, and helical twist. By combining sequence optimization existing repeats de novo capping structures, we designed leucine-rich (LRRs) from ribonuclease inhibitor (RI) family assemble into structures with predefined...
Abstract Transmission-blocking vaccines have the potential to be key contributors malaria elimination. Such elicit antibodies that inhibit parasites during their development in Anopheles mosquitoes, thus breaking cycle of transmission. To date, characterization humoral responses Plasmodium falciparum transmission-blocking vaccine candidate Pfs25 has largely been conducted pre-clinical models. Here, we present molecular analyses human antibody generated a clinical trial evaluating...
Abstract Amine transaminase (ATA) catalyse enantioselectively the direct amination of ketones, but insufficient stability during catalysis limits their industrial applicability. Recently, we revealed that ATAs suffer from substrate‐induced inactivation mechanism involving dissociation enzyme–cofactor intermediate. Here, report on engineering cofactor‐ring‐binding element, which also shapes active‐site entrance. Only two point mutations in this motif improved temperature and catalytic both...
The extensive glycosylation of HIV-1 envelope (Env) glycoprotein leaves few glycan-free holes large enough to admit broadly neutralizing antibodies (bnAb). Consequently, most bnAbs must inevitably make some glycan contacts and avoid clashes with others. To investigate how Env maturation regulates HIV sensitivity bnAbs, we modified pseudovirus (PV) using various glycoengineering (GE) tools. Promoting the α-2,6 sialic acid (SA) termini increased PV two that target V2 apex one interface between...
ABSTRACT Homomeric coiled‐coils can self‐assemble into a wide range of structural states with different helix topologies and oligomeric states. In this study, we have combined de novo structure modeling stability calculations to simultaneously predict homomeric coiled‐coils. For dimers an asymmetric protocol was developed. Modeling without symmetry constraints showed that backbone asymmetry is important for the formation parallel dimeric Collectively, our results demonstrate high‐resolution...
Models generated by de novo structure prediction can be very useful starting points for molecular replacement systems where suitable structural homologues cannot readily identified. Protein–protein complexes and -designed proteins are examples of that challenging to phase. In this study, the potential models protein use as is investigated. The approach demonstrated using homomeric coiled-coil proteins, which excellent model oligomeric systems. Despite stereotypical fold coiled coils, initial...
Chondroadherin (CHAD) is a cartilage matrix protein that mediates the adhesion of isolated chondrocytes. Its core composed 11 leucine-rich repeats (LRR) flanked by cysteine-rich domains. CHAD makes important interactions with collagen as well cell-surface heparin sulfate proteoglycans and α2β1 integrins. The integrin-binding site located in region hitherto unknown structure at C-terminal end CHAD. Peptides based on human (hCHAD) sequence have shown therapeutic potential for treating...
Abstract Chaperones play a central part in the quality control system cells by clearing misfolded and aggregated proteins. The chaperone DnaK acts as sensor for molecular stress recognising short hydrophobic stretches of As level unfolded protein is function stability, we hypothesised that response upon overexpression recombinant proteins would be correlated to stability. Using set mutants λ-repressor with varying thermal stabilities fluorescent reporter system, effect stability on abundance...
Abstract We could demonstrate that the AAA+ unfoldase ClpC together with protein arginine kinase and adaptor McsB, its activator McsA phosphatase YwlE form a unique chaperone system. Here, McsA-activated McsB phosphorylates targets aggregated substrate proteins for extraction unfolding by ClpC. Sub-stoichiometric amounts of enhanced ClpC/McsB/McsA mediated disaggregation facilitated de-phosphorylation arginine-phosphorylated extruded ClpC, allowing subsequent refolding. Interestingly,...
Abstract Chaperones play a central part in the quality control system cells by clearing misfolded and aggregated proteins. The chaperone DnaK acts as sensor for molecular stress recognising short hydrophobic stretches of As level unfolded protein is function stability, we hypothesised that response upon overexpression recombinant proteins would be correlated to stability. Using set mutants λ -repressor with varying thermal stabilities fluorescent reporter system, effect stability on...
Abstract Chaperones play a central part in the quality control system cells by clearing misfolded and aggregated proteins. The chaperone DnaK acts as sensor for molecular stress recognising short hydrophobic stretches of As level unfolded protein is function stability, we hypothesised that response upon overexpression recombinant proteins would be correlated to stability. Using set mutants lambda-repressor with varying thermal stabilities fluorescent reporter system, effect stability on...