Fig. 5: Allosteric inhibition of the p97^R155H disease mutant by triazole inhibitors.

a Binding site of the triazole inhibitors. Gold, blue and white are the structures of p97^R155H | _NSC804515, p97^R155H | _NSC819701, and p97^WT | _NSC799462. Yellow, light green, blue, and red ball representations are for sulfur, fluorine, nitrogen, and oxygen atoms. K615 side chain adopts different conformations when interacting with meta- and para-fluorobenzene rings. b Cryo-EM densities of p97^R155H | _NSC804515 and p97^R155H | _NSC819701. Green, orange, orange-red, and purple are the N-terminal (NTD), D1, D2, and linker domains, respectively. The densities were filtered to 5.0 Å⁻¹ for presentation. The NTD shows in different conformations when bound to the triazole inhibitors. Two p97^R155H | _NSC819701 structures with different NTD conformations, partially up and down conformations, were determined. c Structural superpositions of the p97^R155H | _NSC819701 (blue; State B, down NTD) and p97^R155H | _NSC804515 (light orange; up NTD) (RMSD 0.846 Å). Dark green is the NTD of p97^R155H | _NSC819701. Enlarged view shows the interaction network of the NSC819701 with the surrounding residues of helices α1 J and α1 M. d Interaction between NTD and D1 domain of the p97^R155H | _NSC819701. Dark green is the NTD of p97^R155H | _NSC819701. Gray surfaces are cryo-EM densities of p97^R155H | _NSC819701 in NTD-down conformation. All distances are measured in Å.