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Frank J. Lebeda

Bio: Frank J. Lebeda is an academic researcher from United States Department of the Army. The author has contributed to research in topics: Clostridium botulinum & Neurotoxin. The author has an hindex of 15, co-authored 33 publications receiving 815 citations.

Papers
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Journal ArticleDOI
TL;DR: A new web-server tool estimates Ki values from experimentally determined IC50 values for inhibitors of enzymes and of binding reactions between macromolecules and ligands to enable end users to help gauge the quality of the underlying assumptions used in these calculations.
Abstract: A new web-server tool estimates Ki values from experimentally determined IC50 values for inhibitors of enzymes and of binding reactions between macromolecules (e.g. proteins, polynucleic acids) and ligands. This converter was developed to enable end users to help gauge the quality of the underlying assumptions used in these calculations which depend on the type of mechanism of inhibitor action and the concentrations of the interacting molecular species. Additional calculations are performed for nonclassical, tightly bound inhibitors of enzyme-substrate or of macromolecule-ligand systems in which free, rather than total concentrations of the reacting species are required. Required userdefined input values include the total enzyme (or another target molecule) and substrate (or ligand) concentrations, the Km of the enzyme-substrate (or the Kd of the target-ligand) reaction, and the IC50 value. Assumptions and caveats for these calculations are discussed along with examples taken from the literature. The host database for this converter contains kinetic constants and other data for inhibitors of the proteolytic clostridial neurotoxins (http:// botdb.abcc.ncifcrf.gov/toxin/kiConverter.jsp).

321 citations

Journal ArticleDOI
TL;DR: The crystal structure of serotype A HA33 (HA33/A) at 1.5 A resolution is reported that contains a unique domain organization and a carbohydrate recognition site and suggests that most of the toxin complex consists of a reoccurring beta-trefoil fold.

73 citations

Journal ArticleDOI
TL;DR: The secondary structures, side-chain solvent accessibilities, and superpositioned crystal structures of the A-chain of ricin and four other plant rRNA N-glycosidases (ribosome-inactivating proteins, RIPs) were examined and it is suggested that this exposed region represents a logical starting point for experiments designed to locate neutralizing epitopes in these RIPs.

48 citations

Journal ArticleDOI
01 Nov 1998-Vaccine
TL;DR: It should be possible to develop small peptides that could be useful in the design of future vaccines against these neurotoxins, based on analyses of the X-ray crystal structure of the tetanus neurotoxin Hc fragment.

47 citations

Journal ArticleDOI
01 Dec 1994-Proteins
TL;DR: The neural net program, PHD, predicted that the secondary structures of the neurotoxins were indeed conserved in both single and multiple sequence modes of analysis, and predicted that a conserved state (variable loops) also exists in non‐aligned regions.
Abstract: The primary structures of a family of ten clostridial. Neurotoxins have recently been deduced yet little information is presently available concerning their secondary or tertiary structures. Because the overall similarity percentage of multiply aligned sequences is high, the secondary structures of these metalloendopeptidases are also expected to be conserved. The neural net program, PHD (Rost and Sander, Proc. Natl. Acad. Sci. USA 90:7558–7562, 1993), predicted that the secondary structures of the neurotoxins were indeed conserved in both single and multiple sequence modes of analysis. Predictions for the amounts of helical, extended, and loop states from the single sequence analyses were consistent with previously published data from circular dichroism studies on some of these neurotoxins. In the single analysis mode, only the aligned regions were predicted to show conservation of the three-state structure. In contrast, the multiple sequence analysis predicted that a conserved state (variable loops) also exists in non-aligned regions. Alignments with the primary structure of the prototypic metalloendopeptidase thermolysin showed that about 25% of the residues within this enzyme are similar to those in the neurotoxins. A comparison of thermolysin's known secondary structure with the predictions from this study showed that about 80% of thermolysin's residues could be structurally aligned with those in the neurotoxins. These predictions provide the necessary. Framework to build a homologous low-resolution tertiary structure of the neurotoxin active site that will be essential in the development of synthetic inhibitors. © 1994 Wiley-Liss, Inc.

39 citations


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Journal ArticleDOI
28 Feb 2001-JAMA
TL;DR: People potentially exposed to botulinum toxin should be closely observed, and those with signs of botulism require prompt treatment with antitoxin and supportive care that may include assisted ventilation for weeks or months.
Abstract: ObjectiveThe Working Group on Civilian Biodefense has developed consensus-based recommendations for measures to be taken by medical and public health professionals if botulinum toxin is used as a biological weapon against a civilian population.ParticipantsThe working group included 23 representatives from academic, government, and private institutions with expertise in public health, emergency management, and clinical medicine.EvidenceThe primary authors (S.S.A. and R.S.) searched OLDMEDLINE and MEDLINE (1960–March 1999) and their professional collections for literature concerning use of botulinum toxin as a bioweapon. The literature was reviewed, and opinions were sought from the working group and other experts on diagnosis and management of botulism. Additional MEDLINE searches were conducted through April 2000 during the review and revisions of the consensus statement.Consensus ProcessThe first draft of the working group's consensus statement was a synthesis of information obtained in the formal evidence-gathering process. The working group convened to review the first draft in May 1999. Working group members reviewed subsequent drafts and suggested additional revisions. The final statement incorporates all relevant evidence obtained in the literature search in conjunction with final consensus recommendations supported by all working group members.ConclusionsAn aerosolized or foodborne botulinum toxin weapon would cause acute symmetric, descending flaccid paralysis with prominent bulbar palsies such as diplopia, dysarthria, dysphonia, and dysphagia that would typically present 12 to 72 hours after exposure. Effective response to a deliberate release of botulinum toxin will depend on timely clinical diagnosis, case reporting, and epidemiological investigation. Persons potentially exposed to botulinum toxin should be closely observed, and those with signs of botulism require prompt treatment with antitoxin and supportive care that may include assisted ventilation for weeks or months. Treatment with antitoxin should not be delayed for microbiological testing.

1,659 citations

Journal ArticleDOI
TL;DR: The mechanism of action of three groups of presynaptic neurotoxins that interfere directly with the process of neurotransmitter release is reviewed, whereas presynapses acting on ion channels are not dealt with here.
Abstract: Nerve terminals are specific sites of action of a very large number of toxins produced by many different organisms. The mechanism of action of three groups of presynaptic neurotoxins that interfere directly with the process of neurotransmitter release is reviewed, whereas presynaptic neurotoxins acting on ion channels are not dealt with here. These neurotoxins can be grouped in three large families: 1) the clostridial neurotoxins that act inside nerves and block neurotransmitter release via their metalloproteolytic activity directed specifically on SNARE proteins; 2) the snake presynaptic neurotoxins with phospholipase A(2) activity, whose site of action is still undefined and which induce the release of acethylcholine followed by impairment of synaptic functions; and 3) the excitatory latrotoxin-like neurotoxins that induce a massive release of neurotransmitter at peripheral and central synapses. Their modes of binding, sites of action, and biochemical activities are discussed in relation to the symptoms of the diseases they cause. The use of these toxins in cell biology and neuroscience is considered as well as the therapeutic utilization of the botulinum neurotoxins in human diseases characterized by hyperfunction of cholinergic terminals.

1,196 citations

Journal ArticleDOI
TL;DR: The crystal structure of the entire 1,285 amino acid di-chain neurotoxin was determined and the toxin appears as a hybrid of varied structural motifs and suggests a modular assembly of functional subunits to yield pathogenesis.
Abstract: Botulinum neurotoxin type A (BoNT/A) is the potent disease agent in botulism, a potential biological weapon and an effective therapeutic drug for involuntary muscle disorders. The crystal structure of the entire 1,285 amino acid di-chain neurotoxin was determined at 3.3 A resolution. The structure reveals that the translocation domain contains a central pair of alpha-helices 105 A long and a approximately 50 residue loop or belt that wraps around the catalytic domain. This belt partially occludes a large channel leading to a buried, negative active site--a feature that calls for radically different inhibitor design strategies from those currently used. The fold of the translocation domain suggests a mechanism of pore formation different from other toxins. Lastly, the toxin appears as a hybrid of varied structural motifs and suggests a modular assembly of functional subunits to yield pathogenesis.

737 citations

Journal ArticleDOI
TL;DR: This review introduces basic immunological concepts required to understand the mechanisms that rule the potential claimed immunostimulatory activity of polysaccharides and critically presents a literature survey on the structural features of the poly Saccharide and reported immunostIMulatory activity.

664 citations

Journal ArticleDOI
TL;DR: A deep learning based model that uses only sequence information of both targets and drugs to predict DT interaction binding affinities is proposed, outperforming the KronRLS algorithm and SimBoost, a state‐of‐the‐art method for DT binding affinity prediction.
Abstract: Motivation The identification of novel drug-target (DT) interactions is a substantial part of the drug discovery process. Most of the computational methods that have been proposed to predict DT interactions have focused on binary classification, where the goal is to determine whether a DT pair interacts or not. However, protein-ligand interactions assume a continuum of binding strength values, also called binding affinity and predicting this value still remains a challenge. The increase in the affinity data available in DT knowledge-bases allows the use of advanced learning techniques such as deep learning architectures in the prediction of binding affinities. In this study, we propose a deep-learning based model that uses only sequence information of both targets and drugs to predict DT interaction binding affinities. The few studies that focus on DT binding affinity prediction use either 3D structures of protein-ligand complexes or 2D features of compounds. One novel approach used in this work is the modeling of protein sequences and compound 1D representations with convolutional neural networks (CNNs). Results The results show that the proposed deep learning based model that uses the 1D representations of targets and drugs is an effective approach for drug target binding affinity prediction. The model in which high-level representations of a drug and a target are constructed via CNNs achieved the best Concordance Index (CI) performance in one of our larger benchmark datasets, outperforming the KronRLS algorithm and SimBoost, a state-of-the-art method for DT binding affinity prediction. Availability and implementation https://github.com/hkmztrk/DeepDTA. Supplementary information Supplementary data are available at Bioinformatics online.

634 citations