Sealy Center for Structural Biology and Molecular Biophysics

Galveston, TX, United States

Sealy Center for Structural Biology and Molecular Biophysics

Galveston, TX, United States
Time filter
Source Type

Maleki S.J.,U.S. Department of Agriculture | Teuber S.S.,University of California at Davis | Cheng H.,U.S. Department of Agriculture | Chen D.,Sealy Center for Structural Biology and Molecular Biophysics | And 4 more authors.
Allergy: European Journal of Allergy and Clinical Immunology | Year: 2011

Background: Cross-reactivity between peanuts and tree nuts implies that similar immunoglobulin E (IgE) epitopes are present in their proteins. Objective: To determine whether walnut sequences similar to known peanut IgE-binding sequences, according to the property distance (PD) scale implemented in the Structural Database of Allergenic Proteins, react with IgE from sera of patients with allergy to walnut and/or peanut. Methods: Patient sera were characterized by western blotting for IgE binding to nut protein extracts and to peptides from walnut and peanut allergens, similar to known peanut epitopes as defined by low PD values, synthesized on membranes. Competitive enzyme-linked immunosorbent assay (ELISA) was used to show that peanut and predicted walnut epitope sequences compete with purified Ara h 2 for binding to IgE in serum from a cross-reactive patient. Results: Sequences from the vicilin walnut allergen Jug r 2, which had low PD values to epitopes of the peanut allergen Ara h 2, a 2S albumin, bound to IgE in sera from five patients who reacted to either walnut or peanut or both. A walnut epitope recognized by sera from six patients mapped to a surface-exposed region on a model of the N-terminal pro-region of Jug r 2. This predicted walnut epitope competed for IgE binding to Ara h 2 in serum as well as the known IgE epitope from Ara h 2. Conclusions: Sequences with low PD value (<8.5) to known IgE epitopes could contribute to cross-reactivity between allergens. This further validates the PD scoring method for predicting cross-reactive epitopes in allergens. © 2011 John Wiley & Sons A/S.

Schein C.H.,Sealy Center for Structural Biology and Molecular Biophysics | Ivanciuc O.,Sealy Center for Structural Biology and Molecular Biophysics | Midoro-Horiuti T.,University of Texas Medical Branch | Goldblum R.M.,Sealy Center for Structural Biology and Molecular Biophysics | And 2 more authors.
Bioinformatics and Biology Insights | Year: 2010

Recent progress in the biochemical classification and structural determination of allergens and allergen-antibody complexes has enhanced our understanding of the molecular determinants of allergenicity. Databases of allergens and their epitopes have facilitated the clustering of allergens according to their sequences and, more recently, their structures. Groups of similar sequences are identified for allergenic proteins from diverse sources, and all allergens are classified into a limited number of protein structural families. A gallery of experimental structures selected from the protein classes with the largest number of allergens demonstrate the structural diversity of the allergen universe. Further comparison of these structures and identification of areas that are different from innocuous proteins within the same protein family can be used to identify features specific to known allergens. Experimental and computational results related to the determination of IgE binding surfaces and methods to define allergen-specific motifs are highlighted.

Chen D.,Sealy Center for Structural Biology and Molecular Biophysics | Ma L.,University of Houston | Kanalas J.J.,Mission Pharmacal Company | Gao J.,Mission Pharmacal Company | And 8 more authors.
Bioorganic and Medicinal Chemistry | Year: 2012

Edema factor (EF) toxin of Bacillus anthracis (NIAID category A), and several other toxins from NIAID category B Biodefense target bacteria are adenylyl cyclases or adenylyl cyclase agonists that catalyze the conversion of ATP to 3′,5′-cyclic adenosine monophosphate (cAMP). We previously identified compound 1 (3-[(9-oxo-9H-fluorene-1-carbonyl)-amino]-benzoic acid), that inhibits EF activity in cultured mammalian cells, and reduces diarrhea caused by enterotoxigenic Escherichia coli (ETEC) at an oral dosage of 15 μg/mouse. Here, molecular docking was used to predict improvements in potency and solubility of new derivatives of compound 1 in inhibiting edema toxin (ET)-catalyzed stimulation of cyclic AMP production in murine monocyte-macrophage cells (RAW 264.7). Structure-activity relationship (SAR) analysis of the bioassay results for 22 compounds indicated positions important for activity. Several derivatives demonstrated superior pharmacological properties compared to our initial lead compound, and are promising candidates to treat anthrax infections and diarrheal diseases induced by toxin-producing bacteria. © 2011 Elsevier Ltd. All rights reserved.

Schein C.H.,Foundation for Applied Molecular Evolution | Schein C.H.,University of Texas Medical Branch | Rowold D.,Foundation for Applied Molecular Evolution | Choi K.H.,University of Texas Medical Branch | Choi K.H.,Sealy Center for Structural Biology and Molecular Biophysics
Bioorganic and Medicinal Chemistry | Year: 2015

Coxsackie virus A24 (CVA24), a causative agent of acute hemorrhagic conjunctivitis, is a prototype of enterovirus (EV) species C. The RNA polymerase (3Dpol) of CVA24 can uridylylate the viral peptide linked to the genome (VPg) from distantly related EV and is thus, a good model for studying this reaction. Once UMP is bound, VPgpU primes RNA elongation. Structural and mutation data have identified a conserved binding surface for VPg on the RNA polymerase (3Dpol), located about 20Å from the active site. Here, computational docking of over 60,000 small compounds was used to select those with the lowest (best) specific binding energies (BE) for this allosteric site. Compounds with varying structures and low BE were assayed for their effect on formation of VPgU by CVA24-3Dpol. Two compounds with the lowest specific BE for the site inhibited both uridylylation and formation of VPgpolyU at 10-20μM. These small molecules can be used to probe the role of this allosteric site in polymerase function, and may be the basis for novel antiviral compounds. © 2015 Elsevier Ltd.

Bruce N.J.,University of Manchester | Chen D.,Sealy Center for Structural Biology and Molecular Biophysics | Dastidar S.G.,Sealy Center for Structural Biology and Molecular Biophysics | Marks G.E.,University of Manchester | And 2 more authors.
Peptides | Year: 2010

Accumulation and aggregation of the 42-residue amyloid-β (Aβ) protein fragment, which originates from the cleavage of amyloid precursor protein by β and γ secretase, correlates with the pathology of Alzheimer's disease (AD). Possible therapies for AD include peptides based on the Aβ sequence, and recently identified small molecular weight compounds designed to mimic these, that interfere with the aggregation of Aβ and prevent its toxic effects on neuronal cells in culture. Here, we use molecular dynamics simulations to compare the mode of interaction of an active (LPFFD) and inactive (LHFFD) β-sheet breaker peptide with an Aβ fibril structure from solid-state NMR studies. We found that LHFFD had a weaker interaction with the fibril than the active peptide, LPFFD, from geometric and energetic considerations, as estimated by the MM/PBSA approach. Cluster analysis and computational alanine scanning identified important ligand-fibril contacts, including a possible difference in the effect of histidine on ligand-fibril π-stacking interactions, and the role of the proline residue in establishing contacts that compete with those essential for maintenance of the inter-monomer β-sheet structure of the fibril. Our results show that molecular dynamics simulations can be a useful way to classify the stability of docking sites. These mechanistic insights into the ability of LPFFD to reverse aggregation of toxic Aβ will guide the redesign of lead compounds, and aid in developing realistic therapies for AD and other diseases of protein aggregation. © 2010 Elsevier Inc. All rights reserved.

Nesbit J.B.,U.S. Department of Agriculture | Hurlburt B.K.,U.S. Department of Agriculture | Schein C.H.,Sealy Center for Structural Biology and Molecular Biophysics | Schein C.H.,University of Texas Medical Branch | And 3 more authors.
Molecular Nutrition and Food Research | Year: 2012

Scope: Ara h 1 from roasted peanut binds higher levels of serum immunoglobulin E than raw peanuts and this is likely due to the Maillard reaction. While Ara h 1 linear IgE epitopes have been mapped, the presence and importance of structural epitopes is not clear. Methods and results: Mass spectrometry, immunoblot, ELISA, circular dichroism (CD), and structural analysis were used to compare structural and subsequent IgE-binding differences in Ara h 1 purified from raw (N) and roasted peanuts (R) and denatured Ara h 1 (D). Although N and R had similar CD spectra, the latter bound significantly more IgE. Decreased IgE binding was seen with the loss of secondary structure. This same IgE-binding pattern [R > N > D] was seen for the sera of ten peanut allergic patients. While the majority of linear epitopes are located on surface and structured regions of Ara h 1, our study shows that conformational epitopes of Ara h 1 bind better to IgE than linear epitopes. Conclusion: Enhanced IgE binding to roasted Ara h 1 could be due to alterations such as chemical modifications to individual amino acids or increased epitope exposure. IgE binding is significantly reduced with loss of structure. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Loading Sealy Center for Structural Biology and Molecular Biophysics collaborators
Loading Sealy Center for Structural Biology and Molecular Biophysics collaborators