RESUMO
The ribosome represents a major target for antibacterial drugs. Being a complex molecular machine, it offers many potential sites for functional interference. The high-resolution structures of ribosome in complex with various antibiotics provide a unique data set for understanding the universal features of drug-binding pockets on the ribosome. In this work, we have analyzed the structural and evolutionary properties of 65 antibiotic binding sites (ABSs) in the ribosome. We compared these sites to similar-size computed pockets extracted from the small and large ribosomal subunits. Based on this analysis, we defined properties of the known drug-binding sites, which constitute the signature of a 'druggable' site. The most noticeable properties of the ABSs are prevalence of non-paired bases, a strong bias in favor of unusual syn conformation of the RNA bases and an unusual sugar pucker. We propose that despite the different geometric and chemical properties of diverse antibiotics, their binding sites tend to have common attributes that possibly reflect the potency of the pocket for binding small molecules. Finally, we utilized the ensemble of properties to derive a druggability index, which can be used in conjunction with site functionality information to identify new drug-binding sites on the ribosome.
Assuntos
Antibacterianos/química , Subunidades Ribossômicas Maiores de Bactérias/química , Subunidades Ribossômicas Menores de Bactérias/química , Sítios de Ligação , Desenho de Fármacos , Evolução Molecular , Ligantes , Modelos Moleculares , RNA Ribossômico/químicaRESUMO
Alternative splicing is regulated by splicing factors that serve as positive or negative effectors, interacting with regulatory elements along exons and introns. Here we present a novel computational method for genome-wide mapping of splicing factor binding sites that considers both the genomic environment and the evolutionary conservation of the regulatory elements. The method was applied to study the regulation of different alternative splicing events, uncovering an interesting network of interactions among splicing factors.
Assuntos
Processamento Alternativo/genética , Mapeamento Cromossômico , Biologia Computacional/métodos , Genoma/genética , Proteínas de Ligação a RNA/metabolismo , Algoritmos , Animais , Sequência de Bases , Sítios de Ligação , Éxons/genética , Genoma Humano/genética , Humanos , Camundongos , Especificidade de Órgãos , Reprodutibilidade dos TestesRESUMO
The ribosome is a complex molecular machine that offers many potential sites for functional interference, therefore representing a major target for antibacterial drugs. The growing number of high-resolution structures of ribosomes from different organisms, in free form and in complex with various ligands, provides unique data for structural and comparative analyses of RNA structures. We model the ribosome structure as a network, where nucleotides are represented as nodes and intermolecular interactions as edges. As shown previously for proteins, we found that the major functional sites of the ribosome exhibit significantly high centrality measures. Specifically, we demonstrate that mutations that strongly affect ribosome function and assembly can be distinguished from mild mutations based on their network properties. Furthermore, we observed that closeness centrality of the rRNA nucleotides is highly conserved in the bacteria, suggesting the network representation as a comparative tool for the ribosome analysis. Finally, we suggest a global topology perspective to characterize functional sites and to reveal the unique properties of the ribosome.
