Fig. 1. CRBN^open is allosterically modulated to CRBN^closed by pomalidomide.

(A) ~3.5-Å-resolution cryo-EM reconstruction of CRBN-DDB1 in the unliganded apo form. The Lon domain (tan) is separated from the TBD (red), while the helical bundle (HB, light red) mediates interaction with DDB1, composed of beta propeller A (BPA, light blue), beta propeller B (BPB, medium blue), and beta propeller C (BPC, steel blue). CRBN and DDB1 are thresholded independently to illustrate important features. To the right, a ribbon representation of the CRBN-DDB1 complex modeled from density is shown (same color scheme as on the left). The sensor loop is denoted as a dotted magenta line extending away from the TBD domain. (B) The unsharpened cryo-EM map shows the path of the sensor loop, which interacts with the HB and BPA of DDB1. (C) Surface representation of the ~3.9-Å-resolution cryo-EM reconstruction of CRBN-DDB1 in the closed form in complex with pomalidomide. The N-terminal belt (orange) wraps around the TBD domain. To the right, a ribbon representation of CRBN-DDB1^ΔBPB in complex with pomalidomide is shown, with the sensor loop (magenta) adopting a β-hairpin organization that is tightly packed between the TBD and Lon domains. (D) A detailed view of the density corresponding to pomalidomide (green) and the sensor loop (magenta) in CRBN^closed.