Figure 4

Overall structural comparison of CRBN TBDs in the free and thalidomide-bound forms. (a) Comparison of the (S)- (cyan) and (R)- (magenta) thalidomide-bound forms of CRBN TBD structures. The structural overlay shows no significant structural differences with a small root-mean-square (rms) deviation (0.13 Å). (b) Comparison of the (S)-thalidomide-bound (cyan) form with the free form²⁸ (grey, PDB code 3WX2) of CRBN TBD structures. The rms deviation is 0.45 Å for C_α carbon atoms except for the mobile β2-β3 loop (residues 344–359). (c) Comparison of the (R)-thalidomide-bound (magenta) and free (grey) forms of CRBN TBD structures. The structural overlay shows a large structural deviation in the mobile β2-β3 loop (residues 344–359), although the remainder of the domain cores are similar with a relatively small rms deviation (0.46 Å). (d) Two crystallographically independent molecules A (grey) and B (green) of CRBN TBD in the free form²⁸ superimposed on each other. Nine residues (351–359) of the flexible β2-β3 loop of molecule B were invisible in the current map. The rms deviation is 1.82 Å for all C_α carbon atoms and 0.34 Å for the core domain without the mobile β2-β3 loop (residues 341–361). (e) Structural comparison of the tri-Trp pockets accommodating (S)-thalidomide (yellow) and (R)-thalidomide (green). Middle, superposition of (S)- and (R)-thalidomide-bound tri-Trp pockets. Left, A close-up view of the tri-Trp pocket of mouse CRBN TBD (cyan) bound to (S)-thalidomide (yellow). Right, a close-up view of the tri-Trp pocket of mouse CRBN TBD (magenta) bound to (R)-thalidomide (green). Side chains of key residues forming the tri-Trp pocket are shown as stick models.