Fig. 1: Effect of the V127 polymorphism on the structure of human PrP^C.

a V127/M129 (PDB 6SV2 – green) and wild-type G127/M129 human PrP (PDB 2W9E – light blue²⁹) crystal structures, superimposed in cartoon representation. Residues 125–223 are shown. The r.m.s. deviations of backbone heavy atoms are less than 0.44 Å between these structures. The sidechains of V127 (red) and R164 (blue) are shown as sticks. This figure and the other structural figures were prepared using PyMOL (PyMOL Molecular Graphics System, Schrödinger, LLC). b Side chain packing in the V127/M129 (green) and WT G127/M129 (light blue) β-sheets. The PrP backbone immediately preceding residue 127 in V127/M129 PrP is displaced due to the bulkier valine sidechain at residue 127. The sidechain and backbone positions of residues in the β-sheet are very similar, with the exception of the sidechain of arginine 164 (R164), which due to its close proximity to residue 127 is displaced in the V127 variant. This perturbation (see also Fig. 8) is observed in solution by a marked chemical shift change in the Nε peak arising from the R164 sidechain group in NMR HSQC spectra (Supplementary Fig. 6). c Four-stranded intermolecular anti-parallel β-sheet formed between neighbouring V127/M129 PrP molecules (in green and lime green). d Intermolecular β-sheet contacts in V127/M129 PrP (green) and WT G127/M129 PrP (light blue). The amino acid sidechains of residues found in the intermolecular β-sheet are shown in stick representation, with the residue 127 and 129 polymorphisms in red and yellow respectively. e, f Intermolecular β-sheet hydrogen bonding in V127/M129 (e) and G127/M129 PrP (f). Hydrogen bonds stabilising the intermolecular β-sheet are shown as blue dotted lines, between the amide (blue) and carbonyl (red) groups of the denoted amino acids, with the corresponding distances in Å. The β-sheet interface in the V127/M129 PrP crystal is stabilised by an additional pair of hydrogen bonds between the carbonyls of G126 and amides of A133 (e). The additional hydrogen bond pair between G126 and A133 is not formed in WT G127/M129 PrP as the hydrogen bond distance is too long (7.7 Å) (f).