Figure 6

Comparison of (R)-thalidomides in the free form and in the CRBN-bound form found in the complex crystal. Superposition of the free form of (R)-thalidomide (grey) on the CRBN-bound form of (R)-thalidomide (green) found in the crystal. The free form of (R)-thalidomide has its glutarimide ring in a C4-exo conformation, while (R)-thalidomide (green) bound to the tri-Trp pocket of CRBN displays a twisted conformation (see text). The C4-exo conformation of the free form causes serious steric clash between the phthalimido-1-carbonyl group and the ring carbon atom of Trp383 (2.6 Å indicated by a dotted line). Additionally, short contacts (~3.6 Å) were found between the C4-carbon atom of the glutarimide moiety and ring carbons of Trp383. The twisted conformation of the bound (R)-thalidomide avoids this clash by shifting the phthalimide ring toward the endo direction so that the clashes are relaxed (4.0 Å and 3.8 Å, respectively) in the twisted form.