A5041386784- Chemical Synthesis and Analysis
- Monoclonal and Polyclonal Antibodies Research
- Malaria Research and Control
- HIV Research and Treatment
- Protein Structure and Dynamics
- Enzyme Structure and Function
- Mosquito-borne diseases and control
- Glycosylation and Glycoproteins Research
- Complement system in diseases
- Peptidase Inhibition and Analysis
- Supramolecular Self-Assembly in Materials
- Protein purification and stability
- RNA and protein synthesis mechanisms
- Trypanosoma species research and implications
- Bacteriophages and microbial interactions
- Invertebrate Immune Response Mechanisms
- Mass Spectrometry Techniques and Applications
- Amyloidosis: Diagnosis, Treatment, Outcomes
- Neuropeptides and Animal Physiology
- Cellular transport and secretion
- Influenza Virus Research Studies
- vaccines and immunoinformatics approaches
- Cell Adhesion Molecules Research
- Nanocluster Synthesis and Applications
- Biochemical and Molecular Research
Scripps Research Institute
2015-2023
Pfizer (United States)
2021-2022
La Jolla Alcohol Research
2022
Vrije Universiteit Brussel
2011-2014
VIB-VUB Center for Structural Biology
2011-2013
Characterizing polyclonal antibody responses via currently available methods is inherently complex and difficult. Mapping epitopes in an immune response typically incomplete, which creates a barrier to fully understanding the humoral antigens hinders rational vaccine design efforts. Here, we describe method of characterizing by using electron microscopy, applied this immunization rabbits with HIV-1 envelope glycoprotein candidate, BG505 SOSIP.664. We detected known within sera revealed how...
The effectiveness of the annual influenza vaccine has declined in recent years, especially for H3N2 component, and is a concern global public health. A major cause this lack been attributed to egg-based production process. Substitutions on hemagglutinin glycoprotein (HA) often arise during virus passaging that change its antigenicity hence effectiveness. Here, we characterize effect prevalent substitution, L194P, egg-passaged viruses. X-ray structural analysis reveals substitution...
Acquired resistance against antimalarial drugs has further increased the need for an effective malaria vaccine. The current leading candidate, RTS,S, is a recombinant circumsporozoite protein (CSP)-based vaccine Plasmodium falciparum that contains 19 NANP repeats followed by thrombospondin repeat domain. Although RTS,S undergone extensive clinical testing and progressed through phase III trials, continued efforts are underway to enhance its efficacy duration of protection. Here, we...
The induction of broad and potent immunity by vaccines is the key focus research efforts aimed at protecting against HIV-1 infection. Soluble native-like envelope glycoproteins have shown promise as vaccine candidates they can induce autologous neutralizing responses in rabbits non-human primates. In this study, monoclonal antibodies were isolated characterized from rhesus macaques immunized with BG505 SOSIP.664 trimer to better understand vaccine-induced antibody responses. Our studies...
An unprecedented spiral structure of the malarial CSP protein in complex with a protective antibody is revealed by cryo-EM.
Abstract The most advanced P. falciparum circumsporozoite protein-based malaria vaccine, RTS,S/AS01 (RTS,S), confers partial protection but with antibody titers that wane relatively rapidly, highlighting the need to elicit more potent and durable responses. Here, we elucidate crystal structures, binding affinities kinetics, in vivo of eight anti-NANP antibodies derived from an RTS,S phase 2a trial encoded by three different heavy-chain germline genes. structures reinforce importance...
The generation of high-quality antibody responses to Plasmodium falciparum (Pf) circumsporozoite protein (PfCSP), the primary surface antigen Pf sporozoites, is paramount development an effective malaria vaccine. Here we present in-depth structural and functional analysis a panel potent antibodies encoded by immunoglobulin heavy chain variable (IGHV) gene IGHV3-33, which among most prevalent families induced in anti-PfCSP immune response targets Asn-Ala-Asn-Pro (NANP) repeat region....
A functional human IgA response to malaria targets a conserved epitope in the N terminus of Plasmodium falciparum circumsporozoite protein.
Potent and durable vaccine responses will be required for control of malaria caused by Plasmodium falciparum (Pf). RTS,S/AS01 is the first, to date, only that has demonstrated significant reduction clinical severe in endemic cohorts Phase 3 trials. Although protective, efficacy declines over time with kinetics paralleling decline antibody Pf circumsporozoite protein (PfCSP). most attention focused on antibodies repeat motifs PfCSP, other regions may play a role protection. Here, we expressed...
The enzyme dihydrofolate reductase (DHFR, E) from Escherichia coli is a paradigm for the role of protein dynamics in catalysis. Previous studies have shown that progresses through kinetic cycle by modulating dynamic conformational landscape presence substrate (DHF), product tetrahydrofolate (THF), and cofactor (NADPH or NADP(+)). This study focuses on quantitative description relationship between fluctuations release, rate-limiting step DHFR NMR relaxation dispersion measurements millisecond...
Lasting protection has long been a goal for malaria vaccines. The major surface antigen on Plasmodium falciparum sporozoites, the circumsporozoite protein (PfCSP), an attractive target vaccine development and most protective antibodies studied to date interact with central NANP repeat region of PfCSP. However, it remains unclear what structural functional characteristics correlate better by one antibody over another. Binding junctional between N-terminal domain repeats proposed result in...
Malaria vaccine candidate RTS,S/AS01 is based on the central and C-terminal regions of circumsporozoite protein (CSP) P. falciparum. mAb397 was isolated from a volunteer in an clinical trial, it protects mice infection by malaria sporozoites. However, originates less commonly used VH3-15 germline gene compared to VH3-30/33 antibodies generally elicited RTS,S NANP repeat region CSP. The crystal structure with NPNA4 peptide shows that NPNA forms type I β-turn main recognition motif. In most...
Water has a profound effect on the dynamics of biomolecules and governs many biological processes, leading to concept that function is slaved solvent within surrounding biomolecule. Protein conformational changes μs-ms time scales are frequently associated with protein function, but little known about behavior protein-bound water these scales. Here we have used NMR relaxation dispersion measurements probe tryptophan indoles in enzyme dihydrofolate reductase (DHFR). We find during structural...
The rate-determining step in the catalytic cycle of E. coli dihydrofolate reductase is tetrahydrofolate (THF) product release, which can occur via an allosteric or intrinsic pathway. pathway, becomes accessible when reduced cofactor NADPH bound, involves transient sampling a higher energy conformational state, greatly increasing dissociation rate as compared to pathway that obtains absent. Although kinetics this process are known, enzyme structure and THF conformation transiently formed...
Malaria is a global health concern, and research efforts are ongoing to develop superior vaccine RTS,S/AS01. To guide immunogen design, we seek comprehensive understanding of the protective humoral response against Plasmodium falciparum (Pf) circumsporozoite protein (PfCSP). In contrast well-studied responses repeat region C-terminus, antibody N-terminal domain PfCSP (N-CSP) remains obscure. Here, characterized molecular recognition functional efficacy N-CSP–specific monoclonal 5D5. The...
The opioid overdose crisis primarily driven by potent synthetic opioids resulted in more than 500,000 deaths the US over last 20 years. Though naloxone, a short-acting medication, remains primary treatment option for temporarily reversing effects, alternative countermeasures are needed. Monoclonal antibodies present versatile therapeutic opportunity that can be tailored to and help prevent post-treatment renarcotization. ultrapotent analog carfentanil is especially concerning due its unique...
CD27 is a tumor necrosis factor (TNF) receptor, which stimulates lymphocytes and promotes their differentiation upon activation by TNF ligand CD70. Activation of the receptor provides costimulatory signal to promote T cell, B NK cell activity facilitate antitumor anti-infection immunity. Aberrant increased focused expression CD70 on many cells renders an attractive therapeutic target for direct killing. However, despite use as drug targets treat cancers, molecular basis atomic details...
Abstract The aggregation pathway of transthyretin (TTR) proceeds through rate-limiting dissociation the tetramer and partial misfolding monomers, which assemble into amyloid structures a downhill polymerization mechanism. structural features aggregation-prone monomeric intermediate are poorly understood. Characterization amyloidogenic intermediates is challenging due to their propensity aggregate at concentrations necessary for studies. NMR relaxation dispersion offers unique opportunity...
Carr-Purcell-Meiboom-Gill (CPMG) relaxation dispersion measurements are a valuable tool for the characterization of structural transitions on micro-millisecond timescale. While measurement (15)N is now routine, with alternative nuclei remain limited. Here we report as well (1)H R2 N23PP/S148A "dynamic knockout" mutant dihydrofolate reductase. The complementary to data many additional residues observed have dispersive behavior nucleus. Simultaneous fitting profiles two increases accuracy...
Abstract The induction of broad and potent immunity by vaccines is the key focus research efforts aimed at protecting against HIV-1 infection. Soluble native-like envelope glycoproteins have shown promise as vaccine candidates they can induce autologous neutralizing responses in rabbits non-human primates. In this study, monoclonal antibodies were isolated characterized from rhesus macaques immunized with BG505 SOSIP.664 trimer to better understand vaccine-induced antibody responses. Our...