Structural insights into leishmanolysins encoded on chromosome 10 of Leishmania (Viannia) braziliensis

BACKGROUND Leishmanolysins have been described as important parasite virulence factors because of their roles in the infection of promastigotes and resistance to host's defenses. Leishmania (Viannia) braziliensis contains several leishmanolysin genes in its genome, especially in chromosome 10. However, the functional impact of such diversity is not understood, but may be attributed partially to the lack of structural data for proteins from this parasite. OBJECTIVES This works aims to compare leishmanolysin sequences from L. (V.) braziliensis and to understand how the diversity impacts in their structural and dynamic features. METHODS Leishmanolysin sequences were retrieved from GeneDB. Subsequently, 3D models were built using comparative modeling methods and their dynamical behavior was studied using molecular dynamic simulations. FINDINGS We identified three subgroups of leishmanolysins according to sequence variations. These differences directly affect the electrostatic properties of leishmanolysins and the geometry of their active sites. We identified two levels of structural heterogeneity that might be related to the ability of promastigotes to interact with a broad range of substrates. MAIN CONCLUSION Altogether, the structural plasticity of leishmanolysins may constitute an important evolutionary adaptation rarely explored when considering the virulence of L. (V.) braziliensis parasites.

Comparative Modeling and Molecular Dynamics Simulation of Substrate Binding in Human Fatty Acid Synthase: Enoyl Reductase and beta-Ketoacyl Reductase Catalytic Domains

Fatty acid synthase (FASN, EC 2.3.1.85), is a multi-enzyme dimer complex that plays a critical role in lipogenesis. This lipogenic enzyme has gained importance beyond its physiological role due to its implications in several clinical conditions-cancers, obesity, and diabetes. This has made FASN an attractive pharmacological target. Here, we have attempted to predict the theoretical models for the human enoyl reductase (ER) and beta-ketoacyl reductase (KR) domains based on the porcine FASN crystal structure, which was the structurally closest template available at the time of this study. Comparative modeling methods were used for studying the structure-function relationships. Different validation studies revealed the predicted structures to be highly plausible. The respective substrates of ER and KR domains-namely, trans-butenoyl and beta-ketobutyryl-were computationally docked into active sites using Glide in order to understand the probable binding mode. The molecular dynamics simulations of the apo and holo states of ER and KR showed stable backbone root mean square deviation trajectories with minimal deviation. Ramachandran plot analysis showed 96.0% of residues in the most favorable region for ER and 90.3% for the KR domain, respectively. Thus, the predicted models yielded significant insights into the substrate binding modes of the ER and KR catalytic domains and will aid in identifying novel chemical inhibitors of human FASN that target these domains.

3-D modeling and molecular dynamics simulation of interleukin-22 from the So-iny mullet, Liza haematocheila

Background: Interleukin-22 (IL-22) plays an important role in the regulation of immune responses. However, little is known about its function or structure in fish. Results: The IL-22 gene was first cloned from So-iny mullet (Liza haematocheila), one of commercially important fish species in China. Then, 3-D structure model of the mullet IL-22 was constructed by comparative modeling method using human IL-22 (1M4R) as template, and a 5 ns molecular dynamics (MD) was studied. The open reading frame (ORF) of mullet IL-22 cDNA was 555 bp, encoding 184 amino acids. The mullet IL-22 shared higher identities with the other fish IL-22 homologs and possessed a conserved IL-10 signature motif at its C-terminal. The mullet IL-22 model possessed six conserved helix structure. PROCHECK, SAVES and Molprobity server analysis confirmed that this model threaded well with human IL-22. Strikingly, analysis with CastP, cons-PPISP server suggested that the cysteines in mullet IL-22 might not be involved in the forming of disulfide bond for structural stabilization, but related to protein-protein interactions. Conclusions: The structure of IL-22 in So-iny mullet (Liza haematocheila) was constructed using comparative modeling method which provide more information for studying the function of fish IL-22.

hpvPDB: An Online Proteome Reserve for Human Papillomavirus

Human papillomavirus (HPV) infection is the leading cause of cancer mortality among women worldwide. The molecular understanding of HPV proteins has significant connotation for understanding their intrusion in the host and designing novel protein vaccines and anti-viral agents, etc. Genomic, proteomic, structural, and disease-related information on HPV is available on the web; yet, with trivial annotations and more so, it is not well customized for data analysis, host-pathogen interaction, strain-disease association, drug designing, and sequence analysis, etc. We attempted to design an online reserve with comprehensive information on HPV for the end users desiring the same. The Human Papillomavirus Proteome Database (hpvPDB) domiciles proteomic and genomic information on 150 HPV strains sequenced to date. Simultaneous easy expandability and retrieval of the strain-specific data, with a provision for sequence analysis and exploration potential of predicted structures, and easy access for curation and annotation through a range of search options at one platform are a few of its important features. Affluent information in this reserve could be of help for researchers involved in structural virology, cancer research, drug discovery, and vaccine design.

Construção do receptor CYSLTR1 por modelagem comparativa / Building of CYSLTR1 receptor by comparative modeling

A asma é caracterizada como um distúrbio inflamatório crônico das vias aéreas, provocada pela contração da musculatura lisa dos bronquíolos, ocasionando obstrução parcial dos mesmos e dificultando a respiração. A Organização Mundial de Saúde (OMS) estima que 300 milhões de pessoas atualmente sofram de asma, sendo que as crianças estão entre as mais acometidas. Somente em 2005, 255.000 pessoas morreram de asma. Dentre os mediadores envolvidos no processo asmático, os leucotrienos cisteínicos, derivados do ácido araquidônico, são considerados os mais potentes entre aqueles envolvidos no processo asmático, indicados como principais mediadores da inflamação reversível das vias aéreas. Nos últimos 20 anos, grandes esforços têm sido realizados para identificar e desenvolver antagonistas dos receptores de leucotrienos na busca de melhorar o tratamento da asma, limitar a sua morbidade, e reduzir os efeitos dos medicamentos atuais. Portanto, o presente estudo propôs a construção de um modelo teórico do receptor do leucotrienos cisteínicos denominado CysLT1 por Modelagem Comparativa. Conclui-se que o modelo obtido através das metodologias computacionais e apresentado no presente estudo pode auxiliar em futuros testes, principalmente em metodologias que empregam ancoragem molecular e de novo design testando, in silico, ligantes de diversas fontes contra o receptor CysLT1.

Asthma is a chronic inflammatory disorder of the airways characterized by contraction of the smooth muscle of the bronchioles, causing their partial obstruction and making it difficult to breathe. The World Health Organization (WHO) estimates that 300 million people currently suffer from asthma, which is more common among children. In 2005 alone, 255,000 people died of asthma. The cysteinyl leukotrienes, derived from arachidonic acid, are considered the most potent mediators of the asthmatic process, being indicated as key mediators of reversible airway inflammation. In the past 20 years, great efforts have been made to identify and develop leukotriene receptor antagonists, in the quest to improve the treatment of asthma, limit its morbidity and reduce the side-effects of current drugs. Therefore, the objective of this study was to build a theoretical model of the cysteinyl leukotriene receptor, CysLT1, by Comparative Modeling. We conclude that the model generated by computational methods and presented in this paper may help in future studies, especially where docking and de novo design are involved, in which new ligands from diverse sources are tested in silico against the CysLT1 receptor.