2lh8

Publication Abstract from PubMed

Summary: While highly conserved throughout evolution, the exact biological function of the prion protein is still unclear. In an effort to identify the potential biological functions of the prion protein we conducted a small-molecule screening assay with the Syrian hamster prion protein (shPrP 90-232). The screen was performed using a library of 149 water-soluble metabolites that are known to pass through the blood-brain barrier. Using a combination of 1D-NMR, fluorescence quenching and surface plasmon resonance we identified thiamine (vitamin B1) as a specific prion ligand with a binding constant of approximately 60 muM. Subsequent studies showed that this interaction is evolutionarily conserved, with similar binding constants being seen for mouse, hamster and human prions. Various protein construct lengths, both with and without the unstructured N-terminal region in the presence and absence of copper, were examined. This indicates the N-terminus has no influence on the protein's ability to interact with thiamine. In addition to thiamine, the more biologically abundant forms of vitamin B1 (thiamine monophosphate and thiamine diphosphate) were also found to bind the prion protein with similar affinity. Heteronuclear NMR experiments were used to determine thiamine's interaction site, which is located between helix 1 and the preceding loop. These data in conjunction with computer-aided docking and molecular dynamics were used to model the thiamine-binding pharmacophore and a comparison with other thiamine binding proteins was performed to reveal the common features of interaction.

The Prion Protein Binds Thiamine.,Perez-Pineiro R, Bjorndahl TC, Berjanskii MV, Hau D, Li L, Huang A, Lee R, Gibbs E, Ladner C, Dong YW, Abera A, Cashman NR, Wishart DS FEBS J. 2011 Aug 16. doi: 10.1111/j.1742-4658.2011.08304.x. PMID:21848803^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.