9OTY
DDB1-CRBN with CK1 alpha, SB-405483, and DEG-47: composite map and model submission
This is a non-PDB format compatible entry.
Summary for 9OTY
| Entry DOI | 10.2210/pdb9oty/pdb |
| EMDB information | 70862 |
| Descriptor | DNA damage-binding protein 1, Protein cereblon, Casein kinase I isoform alpha, ... (6 entities in total) |
| Functional Keywords | e3 ligases, cullin ring ligase, crl4, cereblon, crbn, molecular glues, imids, ligase |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 3 |
| Total formula weight | 172511.82 |
| Authors | Rizvi, Z.,Lander, G.C. (deposition date: 2025-05-27, release date: 2025-11-19, Last modification date: 2026-02-04) |
| Primary citation | Dippon, V.N.,Rizvi, Z.,Choudhry, A.E.,Chung, C.W.,Alkuraya, I.F.,Xu, W.,Tao, X.B.,Jurewicz, A.J.,Schneck, J.L.,Chen, W.,Curnutt, N.M.,Kabir, F.,Chan, K.H.,Queisser, M.A.,Musetti, C.,Dai, H.,Lander, G.C.,Benowitz, A.B.,Woo, C.M. Identification of an allosteric site on the E3 ligase adapter cereblon. Nature, 2026 Cited by PubMed Abstract: Cereblon (CRBN) is the target of thalidomide derivatives that achieve therapeutic efficacy against some haematologic neoplasias by recruiting neosubstrates for degradation. Despite the intense investigation of orthosteric thalidomide derivatives, little is known about alternate binding sites on CRBN. Here we report an evolutionarily conserved cryptic allosteric binding site on CRBN. Small-molecule SB-405483 binds the allosteric site to cooperatively enhance the binding of orthosteric ligands and alter their neosubstrate degradation profiles. A survey of over 100 orthosteric ligands and their degradation targets reveals trends in the classes of compounds and neosubstrates in which degradation outcomes are enhanced or inhibited by SB-405483. Structural investigations provide a mechanistic basis for the effects of the allosteric ligand by shifting the conformational distribution of CRBN to a novel CRBN and increasing the CRBN state. The discovery of a cryptic allosteric binding site on CRBN that alters the functional effects of orthosteric ligands opens new directions with broad implications for improving the selectivity and efficacy of CRBN therapeutics. PubMed: 41565821DOI: 10.1038/s41586-025-09994-w PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3 Å) |
Structure validation
Download full validation report
