Fig. 5: Structure of falcilysin in its open and partially closed conformations.

A, B Structure alignment based on N-halves (panel A) or C-halves (panel B). The partially closed “pC” conformation of FLN is colored in cyan (N-half), blue (linker), and green (C-half); the open conformation of FLN is colored in purple (N-half), yellow (linker), and red (C-half). Rotations of N-half and C-half when transitioning from open to “pC” states are indicated by double-headed arrows. MK-4815 binds to the N-half domain in “pC” conformation next to the hinge helix α13, which makes direct contact with the C-half domain. C Magnified views of the hinge helix from two orthogonal directions. The open and “pC” conformations are aligned based on N-halves and displayed as ribbons following the same color code as in panel (A). During the transition from the “pC” to open conformations, I739 moves towards the position occupied by the K515 side chain in the “pC” state. As a result, the hinge helix is shifted toward the binding pocket of MK-4815. In the “pC” conformation, I513 is 3.6 Å away from MK-4815. In the open conformation, I513 would be too close to MK-4815, causing steric hindrance. Thus, the binding of MK-4815 disfavors open conformation (see text).