Figure 24.

Stereo views of the S1 subpocket in the 2·M_2/up^pro state and the bound substrate P1 group in 2Q6G. The substrate peptide (red cartoon) is visible at the top of the image. (A) The donut-shaped S1 subpocket is lined by Glu166 (orange), His172 (green), His163 (not visible), Ser139 (blue), Phe140 (blue), Leu141 (blue), Asn142 (coral), and the substrate P3 side chain (yellow). The P1 Gln side chain (pink) occupies the “donut hole”, with the open side serving as a solvent-accessible cavity for the Gln amide, thereby reducing the desolvation cost of this group. Many of the residues lining the S1 subpocket play dual roles: The backbone of Glu166 H-bonds with the substrate P3 backbone (thereby directly connecting the β-sheet formed by the substrate and β-hairpin to the subpocket), and Asn142 serves as the gatekeeper of the subpocket. Tyr118 (zone 3) H-bonds with the backbone NH and O of Ser139, and Tyr126 (zone 3) H-bonds with the backbone O of Phe140. (B) Same as A, except showing the solvent-accessible surface lining the S1 subpocket (noting that the subpocket entrance is occluded by Asn142 and the substrate P3 group). (C) Same as B, except showing the rear side of the S1 subpocket.