RESUMEN
The immune system is constantly challenged, being required to protect the organism against a wide variety of infectious pathogens and, at the same time, to avoid autoimmune disorders. One of the most important molecules involved in these events is the Major Histocompatibility Complex class I (MHC-I), responsible for binding and presenting small peptides from the intracellular environment to CD8(+) T cells. The study of peptide:MHC-I (pMHC-I) molecules at a structural level is crucial to understand the molecular mechanisms underlying immunologic responses. Unfortunately, there are few pMHC-I structures in the Protein Data Bank (PDB) (especially considering the total number of complexes that could be formed combining different peptides), and pMHC-I modelling tools are scarce. Here, we present DockTope, a free and reliable web-based tool for pMHC-I modelling, based on crystal structures from the PDB. DockTope is fully automated and allows any researcher to construct a pMHC-I complex in an efficient way. We have reproduced a dataset of 135 non-redundant pMHC-I structures from the PDB (Cα RMSD below 1 Å). Modelling of pMHC-I complexes is remarkably important, contributing to the knowledge of important events such as cross-reactivity, autoimmunity, cancer therapy, transplantation and rational vaccine design.
Asunto(s)
Linfocitos T CD8-positivos/metabolismo , Biología Computacional/métodos , Antígenos de Histocompatibilidad Clase I/metabolismo , Internet , Péptidos/metabolismo , Algoritmos , Secuencia de Aminoácidos , Bases de Datos de Proteínas , Epítopos/química , Epítopos/genética , Epítopos/metabolismo , Antígenos de Histocompatibilidad Clase I/química , Antígenos de Histocompatibilidad Clase I/genética , Humanos , Modelos Moleculares , Péptidos/química , Unión Proteica , Dominios Proteicos , Reproducibilidad de los ResultadosRESUMEN
The CrossTope is a highly curate repository of three-dimensional structures of peptide:major histocompatibility complex (MHC) class I complexes (pMHC-I). The complexes hosted by this databank were obtained in protein databases and by large-scale in silico construction of pMHC-I structures, using a new approach developed by our group. At this moment, the database contains 182 'non-redundant' pMHC-I complexes from two human and two murine alleles. A web server provides interface for database query. The user can download (i) structure coordinate files and (ii) topological and charges distribution maps images from the T-cell receptor-interacting surface of pMHC-I complexes. The retrieved structures and maps can be used to cluster similar epitopes in cross-reactivity approaches, to analyse viral escape mutations in a structural level or even to improve the immunogenicity of tumour antigens. Database URL: http://www.crosstope.com.br.
Asunto(s)
Bases de Datos de Proteínas , Complejo Mayor de Histocompatibilidad/inmunología , Modelos Moleculares , Péptidos/química , Péptidos/inmunología , Animales , Reacciones Cruzadas/inmunología , Cristalografía por Rayos X , Humanos , Almacenamiento y Recuperación de la Información , Ratones , Análisis Multivariante , Diseño de Software , Interfaz Usuario-ComputadorRESUMEN
The Bunyaviridae virus family is composed by five genera, of which the Hantavirus genus is one of the most important representatives. Occasionally, these viruses can be transmitted to humans, giving rise to severe diseases that present high mortality rates. We analyzed the amino acid sequences of the nucleocapsid (N) proteins of 34 different hantaviruses to investigate the potential mechanisms involved in immunogenicity against hantaviruses. Immunogenic epitopes described in the literature through experimental analyses for Sin Nombre (SNV), Puumala (PUUV), and Hantaan (HTNV) viruses' species were retrieved. We identified and characterized the regions believed to be responsible for the induction of immune response in hosts. We found that N protein epitopes described in the literature for PUUV, SNV and HTNV viruses are all located in highly conserved regions of the protein. The high conservation of these regions suggests that a cross-reactive immune response among different hantaviruses can be induced.