The development of transmissible spongiphorm encephalopathies (TSE) is associated with the conversion of the cellular prion protein (PrPc) into the misfolded, pathogenic isoform (PrPSc). In human genetic forms of these diseases, mutations in the globular C-terminal domain of PrPc are hypothesized to favor spontaneous generation of PrPSc in specific brain regions, leading to neuronal cell degeneration and death. Approximately 10-15% of TSEs are associated with mutations. Structural studies of PrP variants may provide us new clues regarding the proposed mechanisms and may help in the identification of “hot spots” in PrPc involved in the pathogenic conversion. We have determined the NMR solution-state structure of the truncated recombinant human (Hu-PrPc, 90-231) PrP carrying the pathological V210I mutation. The V210I mutation is linked to genetic Creutzfeldt-Jakob disease (CJD). The determined structure of the mutant consists of unstructured N-terminal part (residues 90-124) and well-defined C-terminal domain (residues 125-228). Detailed analysis and comparison with the structure of the WT Hu-PrP revealed that although structures share similar global fold, mutations introduces some local structural differences. The observed variations are mostly clustered at the alpha2-alpha3 inter-helical interface and in the beta2-alpha2 loop region. The alteration of conformation of the beta2-alpha2 loop region and the subsequent changes in hydrophobic cluster facilitate intermolecular interactions between PrP proteins. The high-resolution NMR structure offers new clues on the earliest events of the pathogenic conversion process and could be used for the development of antiprion drugs.
COBISS.SI-ID: 4776474
G-rich oligonucleotides with cytosine residues in their sequences can form G-quadruplexes where G-quartets are flanked by GC Watson-Crick base pairs. Solution state nuclear magnetic resonance was used in order to study the folding of the d(G3CT4G3C) oligonucleotide into a G-quadruplex upon addition of 15NH4+ ions. A single ammonium ion binding site was identified between adjacent G-quartets, although three binding sites were expected. A relatively fast movement of ammonium ions from the inner binding site to bulk with the rate constants of 21 s-1 was detected. The remaining potential cation binding sites between G-quartets and GC base pairs are indeed occupied by water molecules. This is the first observation of long-lived water molecules within a G-quadruplex structure.
COBISS.SI-ID: 4651802
We disclosed the preparation and study of 12 new P-stereogenic 1,2-bis[(o-RO-phenyl)(phenyl)phosphino]ethane ligands of our “R-SMS-Phos” series. This overall meticulous study and ligand comparison is valuable for metal-catalyzed asymmetric hydrogenations, and justifies the synthesis and study of large series of a given phosphine. Ligands with marked increase in the reaction rate and enantioselectivity were identified which would help to improve current ligand designs and bring a further insight into the Rh-catalyzed hydrogenation of olefins.
COBISS.SI-ID: 4698650