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Journal ArticleDOI

Structural vaccinology approach to investigate the virulent and secretory proteins of Bacillus anthracis for devising anthrax next-generation vaccine

01 Oct 2020-Journal of Biomolecular Structure & Dynamics (J Biomol Struct Dyn)-Vol. 38, Iss: 16, pp 4895-4905

TL;DR: Abstract Communicated by Ramaswamy H. Sarma is a post-graduate student of electrical engineering at the University of California, Berkeley and a member of the faculty at the California Institute of Technology, Berkeley.

AbstractAbstract Communicated by Ramaswamy H. Sarma

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Citations
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Journal ArticleDOI
TL;DR: The significance of the study deals with the identification of adjuvant (ligand) for human TLRs individually which assist in the development of the optimal highly immunogenic vaccine.
Abstract: Human immune cell toll-like receptors (TLRs) provide a novel chance for the development of the vaccine adjuvant engaging TLR signaling. A library of peptides was developed and peptides structure was generated through homology modeling and refinement. Further, these peptides were subjected to receptor-ligand interaction study against human immune cell TLRs using Schrodinger-suite software. Here, we identified the most potent ligands for each human immune cell receptor and identified it as a potent adjuvant. This work portrays the ability of binding of different known protein adjuvants with human TLRs 1--10. The significance of the study deals with the identification of adjuvant (ligand) for human TLRs individually which assist in the development of the optimal highly immunogenic vaccine.

10 citations

Journal ArticleDOI
TL;DR: A stable multivalent vaccine combining several T-cell and B-cell epitopes of the essential Nipah viral proteins with the help of different ligands and adjuvants which can effectively induce both humoral and cellular immune responses in human is designed.
Abstract: Nipah virus (NPV) is one of the most notorious viruses with a very high fatality rate. Because of the recurrent advent of this virus and its severe neurological implications, often leading to high ...

9 citations

Journal ArticleDOI
TL;DR: The structural basis of the binding mechanism of 3-methyleneisoindolin-1-one molecules with ABA receptors is revealed and Mol26 and Mol25 were identified for the development of specific PYL3 agonists with a vast potential in agriculture to accentuate the ABA like action in plants.
Abstract: Abscisic acid (ABA) although complicated and expensive to produce, plays an important role in signalling responsible for regulation of developmental manifestations such as seed maturation and surviving through stress conditions Hence, development of cost effective molecules with minimal side effects that mimic the functions of ABA is the need of the hour In this agreement, we screened a series of 27 in-house synthesized 3-methyleneisoindolin-1-one molecules over three ABA receptors (PYR1, PYL1, and PYL3) The commercial ABA agonist Pyrabactin was taken as a standard ligand in this study The top three molecules for each receptor were selected and further evaluated to estimate the dynamical contribution and complex stability via Molecular Mechanics-Poisson Boltzmann surface area calculations Two molecules (Mol26 and Mol25) showed higher binding free energy and stable complex conformation for PYL3 in comparison to Pyrabactin This study revealed the structural basis of the binding mechanism of 3-methyleneisoindolin-1-one molecules with ABA receptors Mol26 and Mol25 were identified for the development of specific PYL3 agonists with a vast potential in agriculture to accentuate the ABA like action in plants

8 citations

Journal ArticleDOI
TL;DR: A preliminary phytochemical screening of the EtOH extract of the Pithecellobium dulce fruit peel showed the presence of alkaloids, glycosides, flavonoids, steroids, tannins, saponin and polyphenols.
Abstract: A preliminary phytochemical screening of the EtOH extract of the Pithecellobium dulce fruit peel showed the presence of alkaloids, glycosides, flavonoids, steroids, tannins, saponin and polyphenols. Notable amounts of phenolics and flavonoids were observed in the fruit peel extract. P. dulce fruit feel extract could potentially prevent the ROS damage and oxidative stress. The crude extract displayed higher DPPH (92.44%) and ABTS (94.51%) radical-scavenging activities. The GC–MS analysis of fruit peel extract revealed the presence of 36 bioactive compounds with pinitol, L-Rhamnose and 1, 5-anhydro-6-deoxyhexo-2, 3-diulose being the dominant compound and these might be responsible for the maximum radical-scavenging activities. Among these bioactive compounds, Pinitol was explored with the best drug-likeness properties with suitable pharmacokinetic properties. Docking and dynamics studies of GRP78-pinitol complex showed the minimized binding affinity (−6.8 kcal/mol) and exhibited the stable binding mode. The present results showed that the three lead compounds of P. dulce may act as noble inhibitors for GRP78 and the compounds can be re-designed and synthesized for potential anticancer activity.

1 citations

Journal ArticleDOI
TL;DR: The engineered recombinant protein can be efficaciously considered as a candidate immunogen and proper and stable binding affinity is revealed between epitopic protein and receptors.
Abstract: Bacillus anthracis is a highly infectious bacterium and causes anthrax. It infects warm-blooded mammals, likewise its spores have been weaponized and used in biological warfare which has affected many people. Prevention of anthrax remains a great challenge for clinicians. Vaccination is the most hopeful mode and a new generation of epitope-based vaccines has received extended attention. This kind of recombinant vaccine offers an effective and fast response because of the direct targeting of the immune system. Nowadays, collecting epitopes information via in silico tools are highly accurate and simple. In this regard, a variety of the best bioinformatic servers were applied to identify potential B-cell, T-cell, IFN-γ, IL-10, and IL-4 epitopes with no allergenic nor toxic effect. The High-ranked epitopes were selected and fused to each other by GPGPG and EAAAK linkers. They constructed the scaffold along with the L7/L12 adjuvant and 6xHis-tag. The physicochemical properties, secondary and tertiary structures were evaluated, refined, and confirmed using bioinformatics tools. Desirable levels of IgG1, IgG2, T-cytotoxic, T-helper cells, INF-γ, and interleukins were predicted using immune simulation tool. Furthermore, the molecular docking and dynamic simulation between epitopic protein and receptors revealed proper and stable binding affinity. Overall, the engineered recombinant protein can be efficaciously considered as a candidate immunogen.

References
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Book ChapterDOI
TL;DR: Details are given about protein identification and analysis software that is available through the ExPASy World Wide Web server and the extensive annotation available in the Swiss-Prot database is used.
Abstract: Protein identification and analysis software performs a central role in the investigation of proteins from two-dimensional (2-D) gels and mass spectrometry. For protein identification, the user matches certain empirically acquired information against a protein database to define a protein as already known or as novel. For protein analysis, information in protein databases can be used to predict certain properties about a protein, which can be useful for its empirical investigation. The two processes are thus complementary. Although there are numerous programs available for those applications, we have developed a set of original tools with a few main goals in mind. Specifically, these are: 1. To utilize the extensive annotation available in the Swiss-Prot database wherever possible, in particular the position-specific annotation in the Swiss-Prot feature tables to take into account posttranslational modifications and protein processing. 2. To develop tools specifically, but not exclusively, applicable to proteins prepared by two dimensional gel electrophoresis and peptide mass fingerprinting experiments. 3. To make all tools available on the World-Wide Web (WWW), and freely usable by the scientific community. In this chapter we give details about protein identification and analysis software that is available through the ExPASy World Wide Web server.

6,688 citations

Journal ArticleDOI
15 Feb 2003-Proteins
TL;DR: Geometrical validation around the Cα is described, with a new Cβ measure and updated Ramachandran plot, and Favored and allowed ϕ,ψ regions are also defined for Pro, pre‐Pro, and Gly (important because Gly ϕ‐ψ angles are more permissive but less accurately determined).
Abstract: Geometrical validation around the Calpha is described, with a new Cbeta measure and updated Ramachandran plot. Deviation of the observed Cbeta atom from ideal position provides a single measure encapsulating the major structure-validation information contained in bond angle distortions. Cbeta deviation is sensitive to incompatibilities between sidechain and backbone caused by misfit conformations or inappropriate refinement restraints. A new phi,psi plot using density-dependent smoothing for 81,234 non-Gly, non-Pro, and non-prePro residues with B < 30 from 500 high-resolution proteins shows sharp boundaries at critical edges and clear delineation between large empty areas and regions that are allowed but disfavored. One such region is the gamma-turn conformation near +75 degrees,-60 degrees, counted as forbidden by common structure-validation programs; however, it occurs in well-ordered parts of good structures, it is overrepresented near functional sites, and strain is partly compensated by the gamma-turn H-bond. Favored and allowed phi,psi regions are also defined for Pro, pre-Pro, and Gly (important because Gly phi,psi angles are more permissive but less accurately determined). Details of these accurate empirical distributions are poorly predicted by previous theoretical calculations, including a region left of alpha-helix, which rates as favorable in energy yet rarely occurs. A proposed factor explaining this discrepancy is that crowding of the two-peptide NHs permits donating only a single H-bond. New calculations by Hu et al. [Proteins 2002 (this issue)] for Ala and Gly dipeptides, using mixed quantum mechanics and molecular mechanics, fit our nonrepetitive data in excellent detail. To run our geometrical evaluations on a user-uploaded file, see MOLPROBITY (http://kinemage.biochem.duke.edu) or RAMPAGE (http://www-cryst.bioc.cam.ac.uk/rampage).

3,666 citations

Journal ArticleDOI
TL;DR: This protocol presents a community-wide web-based method using RaptorX (http://raptorx.uchicago.edu/) for protein secondary structure prediction, template-based tertiary structure modeling, alignment quality assessment and sophisticated probabilistic alignment sampling.
Abstract: A key challenge of modern biology is to uncover the functional role of the protein entities that compose cellular proteomes. To this end, the availability of reliable three-dimensional atomic models of proteins is often crucial. This protocol presents a community-wide web-based method using RaptorX ( http://raptorx.uchicago.edu/ ) for protein secondary structure prediction, template-based tertiary structure modeling, alignment quality assessment and sophisticated probabilistic alignment sampling. RaptorX distinguishes itself from other servers by the quality of the alignment between a target sequence and one or multiple distantly related template proteins (especially those with sparse sequence profiles) and by a novel nonlinear scoring function and a probabilistic-consistency algorithm. Consequently, RaptorX delivers high-quality structural models for many targets with only remote templates. At present, it takes RaptorX ∼35 min to finish processing a sequence of 200 amino acids. Since its official release in August 2011, RaptorX has processed ∼6,000 sequences submitted by ∼1,600 users from around the world.

1,276 citations

Journal ArticleDOI
TL;DR: Clinical presentation and course of cases of bioterrorism-related inhalational anthrax, in the District of Columbia, Florida, New Jersey, and New York, are described; survival of patients was markedly higher than previously reported.
Abstract: From October 4 to November 2, 2001, the first 10 confirmed cases of inhalational anthrax caused by intentional release of Bacillus anthracis were identified in the United States. Epidemiologic investigation indicated that the outbreak, in the District of Columbia, Florida, New Jersey, and New York, resulted from intentional delivery of B. anthracis spores through mailed letters or packages. We describe the clinical presentation and course of these cases of bioterrorism-related inhalational anthrax. The median age of patients was 56 years (range 43 to 73 years), 70% were male, and except for one, all were known or believed to have processed, handled, or received letters containing B. anthracis spores. The median incubation period from the time of exposure to onset of symptoms, when known (n=6), was 4 days (range 4 to 6 days). Symptoms at initial presentation included fever or chills (n=10), sweats (n=7), fatigue or malaise (n=10), minimal or nonproductive cough (n=9), dyspnea (n=8), and nausea or vomiting (n=9). The median white blood cell count was 9.8 X 10(3)/mm(3) (range 7.5 to 13.3), often with increased neutrophils and band forms. Nine patients had elevated serum transaminase levels, and six were hypoxic. All 10 patients had abnormal chest X-rays; abnormalities included infiltrates (n=7), pleural effusion (n=8), and mediastinal widening (seven patients). Computed tomography of the chest was performed on eight patients, and mediastinal lymphadenopathy was present in seven. With multidrug antibiotic regimens and supportive care, survival of patients (60%) was markedly higher (<15%) than previously reported.

900 citations

Journal ArticleDOI
20 Sep 2002-Science
TL;DR: It is found that B. anthracis lethal factor selectively induces apoptosis of activated macrophages by cleaving the amino-terminal extension of mitogen-activated protein kinase (MAPK) kinases (MKKs) that activate p38 MAPKs.
Abstract: The bacterium Bacillus anthracis causes the death of macrophages, which may allow it to avoid detection by the innate immune system. We found that B. anthracis lethal factor (LF) selectively induces apoptosis of activated macrophages by cleaving the amino-terminal extension of mitogen-activated protein kinase (MAPK) kinases (MKKs) that activate p38 MAPKs. Because macrophages that are deficient in transcription factor nuclear factor κB (NF-κB) are also sensitive to activation-induced death and p38 is required for expression of certain NF-κB target genes, p38 is probably essential for synergistic induction of those NF-κB target genes that prevent apoptosis of activated macrophages. This dismantling of the p38 MAPK module represents a strategy used by B. anthracis to paralyze host innate immunity.

488 citations