THE 'protein only' hypothesis¹ states that a modified form of normal prion protein triggers infectious neurodegenerative diseases, such as bovine spongiform encephalopathy (BSE), or Creutzfeldt–Jakob disease (CJD) in humans^2–4. Prion proteins are thought to exist in two different conformations⁵: the 'benign' PrP^C form, and the infectious 'scrapie form', PrP^Sc. Knowledge of the three-dimensional structure of PrP^C is essential for understanding the transition to PrP^Sc. The nuclear magnetic resonance (NMR) structure of the autonomously folding PrP domain comprising residues 121–231 (ref. 6) contains a two-stranded anti-parallel β-sheet and three α-helices. This domain contains most of the point-mutation sites that have been linked, in human PrP, to the occurrence of familial prion diseases⁷. The NMR structure shows that these mutations occur within, or directly adjacent to, regular secondary structures. The presence of a β-sheet in PrP(121–231) is in contrast with model predictions of an all-helical structure of PrP^C (ref. 8), and may be important for the initiation of the transition from PrP^C to PrP^Sc.