Fig. 3: Mechanism of opening of RyR1 by atorvastatin.

A H.O.L.E. plot for the three structures. The corresponding pore radii are shown on the right, with the positions of I4937, Q4933, and G4894 indicated. B, C Surface representation of the closed RyR1+atorvastatin structure, showing the atorvastatins from the open RyR1+atorvastatin structure in sticks (red: oxygen; blue: nitrogen; light green: fluor; yellow/green/magenta: carbon for ator1,ator2 and ator3, respectively). The superposition is based on helices S1–S3. Shown are two different views that highlight major steric clashes, especially for Ator2 (green) and Ator3 (magenta). The latter forms a major clash with the side chain of M4818, but even if the side chain were to swing away, there still are clashes with main chain atoms. Thus, binding of these two molecules is not possible in the closed state. Select RyR1 residues are labeled for reference. D local conformational changes between the closed RyR1+atorvastatin (cyan) and the open RyR1+atorvastatin (orange), with the three atorvastatin molecules shown in sticks (colored as in panels (B, C)). This superposition is based on the S1–S3 helices of the pVSD, showing the relative movements of S4, the S4–S5 linker, and the S5’ helix of a neighboring subunit to accommodate the additional statins. E Superposition of the transmembrane regions of the closed and open state RyR1+atorvastatin.