2. Academic Validation
  3. Identification of an allosteric site on the E3 ligase adapter cereblon

Identification of an allosteric site on the E3 ligase adapter cereblon

  • Nature. 2026 Mar;651(8105):482-490. doi: 10.1038/s41586-025-09994-w.
Vanessa N Dippon 1,  Zeba Rizvi # 2,  Anthony E Choudhry # 3,  Chun-Wa Chung 4,  Ibrahim F Alkuraya 1,  Wenqing Xu 1,  Xavier B Tao 1,  Anthony J Jurewicz 3,  Jessica L Schneck 3,  Wenqian Chen 2 5,  Nicole M Curnutt 1,  Farah Kabir 1,  Kwok-Ho Chan 4,  Markus A Queisser 4,  Caterina Musetti 3 6,  Han Dai 3,  Gabriel C Lander 2,  Andrew B Benowitz 7,  Christina M Woo 8 9
Affiliations

Affiliations

  • 1 Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA.
  • 2 Department of Integrative Structural and Computational Biology, Scripps Research, La Jolla, CA, USA.
  • 3 GSK, Research Technologies, Collegeville, PA, USA.
  • 4 GSK, Research Technologies, Stevenage, UK.
  • 5 Genentech, South San Francisco, CA, USA.
  • 6 Bristol Myers Squibb, Lawrenceville, NJ, USA.
  • 7 GSK, Research Technologies, Collegeville, PA, USA. [email protected].
  • 8 Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA. [email protected].
  • 9 Broad Institute, Cambridge, MA, USA. [email protected].
  • # Contributed equally.
PMID: 41565821 DOI: 10.1038/s41586-025-09994-w
Abstract

Cereblon (CRBN) is the target of thalidomide derivatives1 that achieve therapeutic efficacy against some haematologic neoplasias2-4 by recruiting neosubstrates for degradation5-7. 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 CRBNopen to a novel CRBNint and increasing the CRBNclosed 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.

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