Figure 5

Comparison of the bound thalidomide conformations. (a) Phthalimido carbonyl groups of (S)-thalidomide docked into grooves formed at the entrance of the tri-Trp pocket. (S)-thalidomide (yellow stick model) bound to the Tri-Trp hole of CRBN TBD. The phthalimido 1-carbonyl group (labelled with red 1) is docked into the groove formed by the side chains of Trp383 and Trp403. The phthalimido 3-carbonyl group (labelled with red 3) is docked into the groove formed by Trp389 and His381 side chains. The van der Waals surfaces of the two carbonyl groups are shown with dots and labelled with red atom numbers. The grooves for docking with the phthalimido carbonyl groups are indicated with orange arrows. (b) As in a, but for (R)-thalidomide (green stick model) bound to the tri-Trp pocket of the CRBN TBD. (c) Comparison of CRBN-bound thalidomide conformations. (S)-thalidomide superimposed onto (R)-thalidomide with overlapping imide groups, which are linked to CRBN by direct hydrogen bonds and polar interactions. The puckered C4 atoms are separated from each other by 1.0 Å and the puckered C3 atoms by 0.5 Å. The phthalimido groups are shifted from each other by a maximum of 1.0 Å. (d) Comparison of the glutarimide ring conformations of thalidomide molecules in the CRBN-bound and free states in crystals. CRBN-bound (S)-thalidomide (yellow) is superimposed onto the free form (grey) of (S)-thalidomide in the racemic thalidomide crystal (34) with imide groups overlapped. The glutarimide ring of CRBN-bound (S)-thalidomide displays the typical C4-endo puckered conformation. This conformation is similar to the glutarimide ring of free (S)-thalidomide, which displays a slightly twisted C4-endo puckered conformation. The phthalimido group of the CRBN-bound form exhibits a displacement (0.5 Å for the carbonyl groups) from that of the free form with overall rms deviation of the phthalimido groups of 0.9 Å. (e) As in (d) but showing (R)-thalidomides. The glutarimide ring of CRBN-bound (R)-thalidomide (green) displays a twisted (C3-endo-C4-exo-C5-endo) conformation. This highly twisted conformation is in sharp contrast with free (R)-thalidomide (grey) in the racemic thalidomide crystal (34). In contrast to (S)-thalidomide, the phthalimido group of CRBN-bound (R)-thalidomide exhibits marked displacement (1.7 Å for the 1-carbonyl group) relative to the free form with large overall rms deviation (1.4 Å) of the phthalimido groups.