Given the challenge of global antibiotic resistance, the development of new medications is indispensable. Lipid II - bacterial cell wall precursor – is a promising pharmaceutical target for innovative antibiotics, whereas lantibiotic nisin, effectively capturing lipid II’s conservative pyrophosphate group, is a potential prototype of a new generation of antibiotics. Because the structure of membrane-bound lipid II/nisin complex is lacking, we studied their recognition via molecular dynamics (MD) simulations. As a result, the medium-driven dynamics of both partners in their parent environments was explored. The N-terminal 11-residue fragment of nisin, which recognizes lipid II in bacterial membrane, adopts a unique closed-ring conformation only in water solution - this was proven by recent NMR study. In this state, the peptide NH groups of the ring A orient toward a common center, forming a pool of H-bond donors. Based on MD data, it was shown that nisin in this conformation forms the most stable complex with pyrophosphate analogues mimicking the binding determinant of lipid II. Here, we describe the results of the detailed in silico study of nisin1-11 structure and dynamics in different solvents. Efficient conformational sampling and clustering of the MD states based on backbone coordinates and dihedral angles was performed. The results obtained were found to be environment-dependent. These findings may be further employed to improve the peptide structure in order to design its new pharmaceutically applicable forms.
The receptor tyrosine kinase (RTK) superfamily comprises many different cell-surface receptors having similar membrane organization and function with signal transduction occuring in the dimeric state. Insulin receptor (IR) and type 1 insulin-like growth factor receptor (IGF1R) differ from other RTKs being constitutively homodimeric transmembrane glycoproteins, and molecular mechanisms of their activation still remain elusive. Current hypothesis suggests ligand-triggered structural changes in the extracellular domain followed by transmembrane (TM) domains closure and dimerization leading to kinase activity in intracellular segments of the receptor. Using experimental data as constraints, we proposed several atomistic models of dimeric states of IR and IGF-1R TM domains. Molecular dynamics simulations of IR ectodomain revealed noticeable collective movements potentially responsible for closure of its C-termini corresponding to spatial approaching of the following TM helices. Also, we demonstrated that the juxtamembrane part of the IR does not impose strong restrictions on the positioning of TM helices. Finally, we utilized two independent structure prediction methods to generate a series of TM dimer conformations followed by cluster analysis and dimerization free energy estimation to select the best dimer models. Biological relevance of the later was further tested via comparison of the hydrophobic organization of TM helices for both wild-type receptors and two their mutants. Based on these data, the role of several TM segments from other proteins in activation of IR and/or IGF-1R was explained. The elaborated models can be used for rational design of new factors modulating insulin signaling.
The taxonomy of common northern nudibranch molluscs of the genus Dendronotus in the vast cold regions of Eurasia remains largely unknown. Abundant material collected in many localities from the Barents Sea, via the Arctic region, to the north-west Pacific was analysed for the first time. An integrated approach combining morphological and ontogenetic data with molecular four-gene (COI, 16S, H3, and 28S) analysis reveals seven species, including three previously undescribed. Dendronotus frondosus (Ascanius, 1774) and Dendronotus dalli Bergh, 1879 were commonly considered as amphiboreal species; however, according to this study they are restricted to the North Atlantic and the North Pacific, respectively. In the north-west Pacific two new species were discovered, Dendronotus kamchaticus sp. nov. and Dendronotus kalikal sp. nov., that are externally similar to D. frondosus, but that show significant distance according to molecular analysis and are considerably different in radular morphology. In the North Atlantic a new species Dendronotus niveus sp. nov., sibling to North Pacific D. dalli, is revealed. The separate status of North Atlantic Dendronotus lacteus (Thompson, 1840) is confirmed, including considerable range extension. The essential similarity of early ontogenetic stages of radular development common for species with disparate adult radular morphology (such as D. frondosus and D. dalli) is shown, and its importance for taxonomy is discussed.
The elastin binding protein (EBP), a spliced variant of lysosomal β-galactosidase, is the primary receptor of elastin peptides that have been linked to emphysema, aneurysm and cancer progression. The sequences recognized by EBP share the XGXXPG consensus pattern found in numerous matrix proteins, notably in elastin where the VGVAPG motif is repeated. To delineate the elastin binding site of human EBP, we built a homology model of this protein and docked VGVAPG on its surface. Analysis of this model suggested that Gln-97 and Asp-98 were required for interaction with VGVAPG because they contribute to the definition of a pocket thought to represent the elastin binding site of EBP. Additionally, we proposed that Leu-103, Arg-107, and Glu-137 were essential residues because they could interact with VGVAPG itself. Site-directed mutagenesis experiments at these key positions validated our model. This work therefore provides the first structural data concerning the interaction of the VGVAPG with its cognate receptor. The present structural data should now allow the development of EBP-specific antagonists.
A hallmark of neurogenesis in vertebrates is the apical-basal fluctuation of radial glia nuclei. Such a phenomenon, called INM, has been known for decades and is closely associated with mitosis but still puzzles scientists. An impressive step in the molecular understanding of INM has recently been achieved by Tsai and coworkers. Using RNA interference associated with time-lapse imaging, these authors demonstrated a dual motor system that can push/pull the nuclei accordingly with the cell cycle stages.
О внутренних уединенных волнах: распространение, деформации и разрушения.