In the center, the superimposition of Pitstop 2c (yellow) and Pitstop 2d (green) is shown, illustrating the U-shaped (Pitstop 2c) vs. extended (Pitstop 2d) binding mode in the binding pocket of clathrin. On the left, the 1- and 2-naphthyl substitutions (top and bottom, respectively) are shown buried deep within the hydrophobic cavity, represented as a surface. The size of the cavity appears to be large enough to accommodate the naphthalene groups in different orientations. van der Waals interactions stabilize the naphthalene groups in slightly different manners. While the distal ring of 1-naphthyl forms extensive van der Waals interactions with Val-50 and Ile-62, the distal ring of 2-naphthyl mainly forms van der Waals contacts with Leu-82. This difference in the interaction of the naphthalene groups induces a sequential conformational change in the remainder of the Pitstop compounds as shown in the close-up views in (H). As a result, the centers of the 2-aminothiazolone moieties shift approximately 2.4 toward Lys-96. The black arrow indicates that the distal phenoxy ring is forced to adopt different conformations, eventually displacing the DMSO molecule, as shown in (H).
