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Conformational changes in the prion protein (PrP) seem to be responsible for prion diseases. We have used conformation-dependent chemical-shift measurements and rotational-resonance distance measurements to analyze the conformation of solid-state peptides lacking long-range order, corresponding to a region of PrP designated H I . This region is predicted to undergo a transformation of secondary structure in generating the infectious form of the protein. Solid-state NMR spectra of specifically '3C-enriched samples of HI, residues 109-122 (MKHMAGAAAAGAVV) of Syrian hamster PrP, have been acquired under cross-polarization and magic-angle spinning conditions. Samples lyophilized from 50% acetonitrile/50% water show chemical shifts characteristic of a 0-sheet conformation in the region corresponding to residues 112-121, whereas samples lyophilized from hexafluoroisopropanol display shifts indicative of a-helical secondary structure in the region corresponding to residues 113-1 17. Complete conversion to the helical conformation was not observed and conversion from a-helix back to 0-sheet, as inferred from the solid-state NMR spectra, occurred when samples were exposed to water. Rotational-resonance experiments were performed on seven doubly I3C-labeled H1 samples dried from water. Measured distances suggest that the peptide is in an extended, possibly &strand, conformation. These results are consistent with the experimental observation that P r P can exist in different conformational states and with structural predictions based on biological data and theoretical modeling that suggest that HI may play a key role in the conformational transition involved in the development of prion diseases.