view article
Figure 3
Using structural biology to explain the specificity of CRBN-recruiting heterobifunctional and molecular-glue degraders. (a) Structure of TNG-961 bound to HBS1L/GSPT3 (PDB entry 10ay) compared with CC-885 (PDB entry 5hxb) bound to GSPT1. (b) Insets show comparison of HBS1L and GSPT1 degraders in the presence of either HBS1L or GSPT1 (CRBN not shown in insets). The red X in the second inset shows clashes of TNG-961 with GSPT1, providing proof of TNG-961 selectivity for HBS1L degradation. (c) Cryo-EM of the ternary-complex structure resulting from CDK2–cyclin-E1, compound 4 and CRBN (cyclin-E1 not shown; PDB entry 9d0x). The inset shows the position of compound 4 (CDK2-recruiting heterobifunctional degrader) at the ternary-complex interface. (d) Surface model comparison of degrader-bound CDK2 compared with clashes observed between inhibitor-bound CDK1 and CRBN (PDB entry 4y72) to explain heterobifunctional degrader specificity. Cyclin and ribbon models for proteins are not shown here for ease of visualization. (e) X-ray crystallographic ternary-complex structure of VAV1, MRT-23227 and CRBN (PDB entry 9nfr). Cryo-EM ternary-complex structure of G3BP2, MRT-5702 and CRBN (PDB entry 9os2). Insets show the position and structure of the respective degraders. A partial MRT-23227 degrader structure is shown due to compound flexibility preventing complete structural elucidation. (f) Inset showing the VAV1 SH3c RT-loop in complex with MRT-23227 and CRBN to highlight key interactions in the RT-loop of VAV1 (dark purple) with residues in CRBN (cyan) which are absent in other SH3-domain containing proteins. The inset for G3BP2 and G3BP1 shows residues of G3BP2 (green) which favor ternary-complex formation through specific CRBN residues (for example Q105) compared with G3BP1 (purple). The bottom panel shows differences in G3BP2 and VAV1 recruitment to CRBN via the respective degraders through noncanonical structural motifs and surface complementarity.

Journal logoSTRUCTURAL BIOLOGY
COMMUNICATIONS
ISSN: 2053-230X
Volume 82| Part 12| December 2026|
https://doi.org/10.1107/S2053230X26010897