Interaction between Prion Protein's Copper-Bound Octarepeat Domain and a Charged C-Terminal Pocket Suggests a Mechanism for N-Terminal Regulation.

Copper plays a critical role in prion protein (PrP) physiology. Cu(2+) binds with high affinity to the PrP N-terminal octarepeat (OR) domain, and intracellular copper promotes PrP expression. The molecular details of copper coordination within the OR are now well characterized. Here we examine how Cu(2+) influences the interaction between the PrP N-terminal domain and the C-terminal globular domain. Using nuclear magnetic resonance and copper-nitroxide pulsed double electron-electron resonance, with molecular dynamics refinement, we localize the position of Cu(2+) in its high-affinity OR-bound state. Our results reveal an interdomain cis interaction that is stabilized by a conserved, negatively charged pocket of the globular domain. Interestingly, this interaction surface overlaps an epitope recognized by the POM1 antibody, the binding of which drives rapid cerebellar degeneration mediated by the PrP N terminus. The resulting structure suggests that the globular domain regulates the N-terminal domain by binding the Cu(2+)-occupied OR within a complementary pocket.

Towards a custom chelator for mercury: evaluation of coordination environments by molecular modeling.

A chelator is a molecule which binds a metal or metalloid ion by two or more functional groups to form a stable ring complex known as a chelate. Despite the widespread clinical use of so-called chelation therapy to remove mercury, none of the drugs currently in use have been shown to chelate mercury. Mercury can adopt three common coordination environments: linear diagonal, trigonal planar, and tetrahedral. We have previously discussed some of the structural criteria for optimal binding of mercury in linear-diagonal coordination with thiolate donors (George et al. in Chem. Res. Toxicol. 17:999-1006, 2004). Here we employed density functional theory and X-ray absorption spectroscopy to evaluate the ideal chain length for simple alkane dithiolate chelators of Hg(2+). We have also extended our previous calculations of the optimum coordination geometries to the three-coordinate [Hg(SR)(3)](-) case. Finally, we propose a new chelator "tripod" molecule, benzene-1,3,5-triamidopropanethiolate, or "Trithiopod," which is expected to bind Hg(2+) in three-coordinate geometry with very high affinity.