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Structure paper

TitleIdentification of an allosteric site on the E3 ligase adapter cereblon.
Journal, issue, pagesNature, Year 2026
Publish dateJan 21, 2026
AuthorsVanessa N Dippon / Zeba Rizvi / Anthony E Choudhry / Chun-Wa Chung / Ibrahim F Alkuraya / Wenqing Xu / Xavier B Tao / Anthony J Jurewicz / Jessica L Schneck / Wenqian Chen / Nicole M Curnutt / Farah Kabir / Kwok-Ho Chan / Markus A Queisser / Caterina Musetti / Han Dai / Gabriel C Lander / Andrew B Benowitz / Christina M Woo /
PubMed AbstractCereblon (CRBN) is the target of thalidomide derivatives that achieve therapeutic efficacy against some haematologic neoplasias by recruiting neosubstrates for degradation. Despite the intense ...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.
External linksNature / PubMed:41565821
MethodsEM (single particle) / X-ray diffraction
Resolution2.21 - 3.39 Å
Structure data

EMDB-70776: DDB1-CRBN open NU refine map
Method: EM (single particle) / Resolution: 2.52 Å

EMDB-70777: DDB1-CRBN open local refinement
Method: EM (single particle) / Resolution: 2.4 Å

EMDB-70778: DDB1-CRBNopen with lenalidomide
Method: EM (single particle) / Resolution: 2.52 Å

EMDB-70781: DDB1-CRBN intermediate NU
Method: EM (single particle) / Resolution: 2.71 Å

EMDB-70782: DDB1-CRBN[Closed] with lenalidomide and SB-405483- consensus refinement
Method: EM (single particle) / Resolution: 2.59 Å

EMDB-70783: DDB1-CRBN[Closed] with lenalidomide and SB-405483- Focused refine map
Method: EM (single particle) / Resolution: 2.21 Å

EMDB-70784: Composite map of DDB1-CRBN[Closed] in the presence of Lenalidomide and SB-405483
Method: EM (single particle) / Resolution: 2.59 Å

EMDB-70788: DDB1-CRBN-CK1a with lenalidomide and SB-405483
Method: EM (single particle) / Resolution: 2.92 Å

EMDB-70789: DDB1-CRBN-CK1a with lenalidomide and SB-405483 (Focused map)
Method: EM (single particle) / Resolution: 2.9 Å

EMDB-70790: DDB1-CRBN with casein kinase 1 alpha, lenalidomide, and SB-405483: composite map submission
Method: EM (single particle) / Resolution: 2.84 Å

EMDB-70795: DDB1-CRBN with Ikaros ZF2-3, lenalidomide, and SB-405483: Consensus map
Method: EM (single particle) / Resolution: 2.97 Å

EMDB-70796: DDB1-CRBN with Ikaros(ZF2-3), lenalidomide, and SB-405483: focused map submission
Method: EM (single particle) / Resolution: 3.17 Å

EMDB-70799: DDB1-CRBN with Ikaros ZF2-3, lenalidomide, and SB-405483; composite map submission
Method: EM (single particle) / Resolution: 2.97 Å

EMDB-70801: DDB1-CRBN with CK1a and DEG47
Method: EM (single particle) / Resolution: 2.78 Å

EMDB-70802: DDB1-CRBN with CK1a and DEG-47: focused map on CRBN
Method: EM (single particle) / Resolution: 3.17 Å

EMDB-70803: DDB1-CRBN with CK1A and DEG-47: Focused map on CK1a
Method: EM (single particle) / Resolution: 3.39 Å

EMDB-70804: DDB1-CRBN with CK1a and DEG47: Composite map submission
Method: EM (single particle) / Resolution: 2.78 Å

EMDB-70827: DDB1-CRBN with CK1a, SB-405483, and DEG-47- consensus map submission
Method: EM (single particle) / Resolution: 2.8 Å

EMDB-70835: DDB1-CRBN with CK1a, SB-405483, and DEG-47: focused map on CRBN
Method: EM (single particle) / Resolution: 3.03 Å

EMDB-70836: DDB1-CRBN with CK1 alpha, SB-405483, and DEG-47: Focused map on CK1 alpha
Method: EM (single particle) / Resolution: 3.08 Å

70862

9oty

EMDB-70862, PDB-9oty:
DDB1-CRBN with CK1 alpha, SB-405483, and DEG-47: composite map and model submission
Method: EM (single particle) / Resolution: 3.0 Å

EMDB-70865: DDB1-CRBN with ikaros(ZF2) and DEG47- consensus map submission
Method: EM (single particle) / Resolution: 2.69 Å

EMDB-70866: DDB1-CRBN with Ikaros(ZF2) and DEG-47: focused map submission
Method: EM (single particle) / Resolution: 2.96 Å

70867

9ouk

EMDB-70867, PDB-9ouk:
DDB1-CRBN with Ikaros(ZF2) and DEG-47: composite map and model submission
Method: EM (single particle) / Resolution: 2.69 Å

EMDB-70868: DDB1-CRBN with ikaros, SB-405483, and DEG-47: consensus map submission
Method: EM (single particle) / Resolution: 2.97 Å

EMDB-70869: DDB1-CRBN with ikaros(ZF2) with SB-405483, and DEG-47: Focused map submission
Method: EM (single particle) / Resolution: 3.17 Å

70870

9oul

EMDB-70870, PDB-9oul:
DDB1-CRBN with Ikaros(ZF2), SB-405483, and DEG-47: composite map and model submission
Method: EM (single particle) / Resolution: 2.97 Å

PDB-9sfm:
Crystal structure of Cereblon-DDB1 in complex with SB-405483 and Lenalidomide
Method: X-RAY DIFFRACTION / Resolution: 2.39 Å

Chemicals

ChemComp-ZN:
Unknown entry

PDB-1ceh:
STRUCTURE AND FUNCTION OF THE CATALYTIC SITE MUTANT ASP99ASN OF PHOSPHOLIPASE A2: ABSENCE OF CONSERVED STRUCTURAL WATER

PDB-1ceg:
CEPHALOTHIN COMPLEXED WITH DD-PEPTIDASE

PDB-1cek:
THREE-DIMENSIONAL STRUCTURE OF THE MEMBRANE-EMBEDDED M2 CHANNEL-LINING SEGMENT FROM THE NICOTINIC ACETYLCHOLINE RECEPTOR BY SOLID-STATE NMR SPECTROSCOPY

ChemComp-EDO:
1,2-ETHANEDIOL

ChemComp-LVY:
S-Lenalidomide

ChemComp-HOH:
WATER

Source
  • homo sapiens (human)
KeywordsLIGASE / E3 ligases / Cullin RING Ligase / CRL4 / Cereblon / CRBN / molecular glues / IMiDs / Ikaros / E3 ubiquitin ligase / substrate receptor / IMiDs (immunomodulatory drugs) / Allosteric modulator

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