Do we still need crystallography? A case study in targeted protein degradation, Presented by: Gabriel Lander, Ph.D., Professor, Integrative Structural and Computational Biology, Scripps Research

January 10, 2023
12 p.m. to 1 p.m.
3232 SW Research Drive
Portland, Oregon 97239
Room: M1441 Vollum Auditorium
Contact Information
CPB Seminar: Dr. Gabriel Lander, Ph.D.
CPB Winter 2023 Seminar Series: Gabriel Lander, Ph.D.


The attainable resolution of structures determined by cryo-EM continues to increase, making this technique an attractive replacement for crystallography. Here, we will explore the utility of both cryo-EM and crystallographic approaches in exploring a protein of high biomedical importance: the cereblon (CRBN) is a ubiquitin ligase (E3) substrate receptor. This protein is co-opted by CRBN E3 ligase modulatory drug (CELMoD) agents that target therapeutically relevant proteins for degradation. Prior crystallographic studies defined the drug-binding site within CRBN's thalidomide-binding domain (TBD), but the allostery of drug-induced neosubstrate binding remained unclear. Cryo-electron microscopy analyses of the DNA damage-binding protein 1 (DDB1)-CRBN in the absence and presence of CELMoD compounds showed that association of CELMoD compounds to the TBD is necessary and sufficient for triggering an allosteric rearrangement from an open conformation to the canonical closed conformation. The neosubstrate Ikaros only stably associates with the closed CRBN conformation, illustrating the importance of allostery for CELMoD compound efficacy and informing structure-guided design strategies to improve therapeutic efficacy.