Annual Review 2024-2025

Cereblon variant. Combining X-ray crystallography data collected using Diamond’s I04 and I24 beamlines, they demonstrated that the structure of their Cereblon variant matched ones previously collected by other groups, but the new crystals achieved higher resolution. Cereblon changes shape when bound to different drugs, and the team also collected Small-Angle X-ray Scattering (SAXS) data at beamline B21 to study how shapeshifting varies between different drug candidates. Together, these findings reveal that the new Cereblon variant is amenable to structural analysis, which could facilitate future research into this promising class of protein- degrading drugs. DOI: 10.1038/s41467-024-52871-9 A N N U A L R E V I E W 2 0 2 4 / 2 5 M A C R OMO L E C U L A R C RY S TA L L O G R A P H Y G R O U P 20 Above: Crystal structure of CRBNmidi in the apo state, containing Lon (yellow), HB (orange) and TBD (red) domains. The mutated residues are indicated (blue), the unresolved region containing the GSG linker is shown as blue dashed line, and Zn2+ is shown as a purple sphere. Bottom: Dimensionless Kratky Plot generated from SAXS data of apo CRBNmidi (black) and CRBNmidi bound to mezigdomide (green), lenalidomide (blue), Boc-VcN (red), or Boc-AcQ (orange). First derivative of turbidity of thermal denaturation for CRBNmidi in the absence (black) or presence of binders lenalidomide (blue), Boc-VcN (red), or Boc-AcQ (orange). Dimensionless Kratky Plot of CRBNmidi +/- binders Thermal denaturation of CRBNmidi +/- binders q*Rg Temperature (°C) (q*Rg) 2 xl(q)/l(0) Turbidity first derivative