STRUCTURE DETERMINATION OF RPRP(90 231)

University Of California San Francisco, San Francisco CA

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Abstract

We have determined the structure of a recombinant fragment (90-231) of Syrian hamster PrP gene product using 3 dimensional heteronuclear NMR. Prions are infectious particles that cause fatal neurodegenerative disorders in humans and animals, such as scrapie in sheep, mad cow disease, and kuru, Cruetzfeld-Jakob, Gerstmann-Staussler-Scheinker disease, and fatal familial insomnia in humans. The diseases' process is unusual in that it is propagated by the change of the conformation of prion proteins from the normal cellular form (PrPc, predominantly alpha helical) to the abnormal aggregated beta-sheet form (PrP Scrapie). The determination of Prp structure is important for both the understanding of prion diseases, and drug design. We use heteronuclear NMR techniques and the graphical NMR software Sparky to make the resonance assignment and NOE cross peak assignment for the determination of the PrP(90-231) structure. The structure was refined using Xplor/Aria and Amber force field. We use molecular graphics (MidasPlus) to check the results of our calculations, and display the NMR constraints with the program noeshow. The interactive process of examining the structure and adding in restraints is heavily dependent on graphics since we have such a great deal of spectral overlap.