Skip to content
DraconiticResearch
Search Sources API
197,768 studies31 sourcesUpdated 41 min ago
Peer-reviewedCC BY 4.0ACS Central Science

The Intersection of Allostery and Induced Proximity through the E3 Ligase Cereblon

  • Vanessa N. Dippon1,2
  • Christina M. Woo1,2
  1. 1Harvard University , , 12 Oxford Street , , ,
  2. 2Chemical Biology and Therapeutics Science, Broad Institute Affiliate Member, , 415 Main Street , , ,
Open at sourcePDFDOICite

Abstract

Allostery modulates protein function through domains that are distinct from a protein’s orthosteric active site. In a therapeutic context, allosteric ligands provide mechanisms to overcome resistance, improve selectivity, and act cooperatively with orthosteric ligands. Separately, induced proximity modalities alter protein function by inducing an interaction between a target protein and an effector protein, like the E3 ligase substrate adapter cereblon (CRBN), which promotes the proteasomal degradation of the target. CRBN ligands that bind at the thalidomide-binding domain have seeded versatile chemical platforms for molecular glue degraders and proteolysis-targeting chimeras (PROTACs). CRBN gains its remarkable inducible substrate scope through conformational shifts that can be mediated by allosteric ligands to alter protein degradation outcomes. We merge the intersection of allostery with induced proximity modalities by examining it first in the context of allosteric pharmacology and second in the context of targeted protein degradation with CRBN, highlighting how lessons learned from allostery with other therapeutic targets could inform emerging opportunities for allosteric modulation of induced proximity events. This intersection of allostery and induced proximity at CRBN conceptually unites two major chemical means of changing protein fate, bringing the potential for highly selective and potent chemical modalities for a greater part of the proteome closer to reality.

Related

  1. Allosteric covalent inhibition of cereblon through cryptic cysteine targeting
    Z. Rizvi, B. E. Nordin, K. T. Symons +5
    bioRxivPreprintAll rights reservedFull textMolecular biology & gene regulationbioRxiv
  2. Rewiring V-type and K-type enzyme allostery through subunit interface mutations
    Apala Chaudhuri, Federica Maschietto, Olivia Enny +2
    BioarxivPreprintCC BYBiophysicsGeneral biologyHAL
  3. Chemically Induced Proximity in Biological Modulation.
    Xiaokang Jin, Chen Zhou, Xiaoyu Zhang
    ACS bio & med chem AuPeer-reviewedCC BY-NC-NDFull textMolecular biology & gene regulationEurope PMC
  4. Chemically Induced Proximity for Targeted Protein O-GlcNAcylation.
    Bowen Ma, Tongyang Xu, Zhihao Guo +1
    Accounts of chemical researchPeer-reviewedCC BYFull textMolecular biology & gene regulationEurope PMC
  5. Cereblon on Steroids: Beyond the Canonical Ligand Space
    A. Herrmann, C. Heim, S. Maiwald +7
    bioRxivPreprintCC BYFull textMolecular biology & gene regulationbioRxiv

Cite

BibTeXRIS
BibTeX
@article{dippon2026intersection,
  title = {{The Intersection of Allostery and Induced Proximity through the E3 Ligase Cereblon}},
  author = {Vanessa N. Dippon and Christina M. Woo},
  journal = {ACS Central Science},
  year = {2026},
  month = oct,
  doi = {10.1021/acscentsci.6c01187},
  url = {https://pubs.acs.org/acscii/article/doi/10.1021/acscentsci.6c01187/5458067/The-Intersection-of-Allostery-and-Induced},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - The Intersection of Allostery and Induced Proximity through the E3 Ligase Cereblon
AU  - Vanessa N. Dippon
AU  - Christina M. Woo
PY  - 2026
DA  - 2026/10/26
JO  - ACS Central Science
DO  - 10.1021/acscentsci.6c01187
UR  - https://pubs.acs.org/acscii/article/doi/10.1021/acscentsci.6c01187/5458067/The-Intersection-of-Allostery-and-Induced
AB  - Allostery modulates protein function through domains that are distinct from a protein’s orthosteric active site. In a therapeutic context, allosteric ligands provide mechanisms to overcome resistance, improve selectivity, and act cooperatively with orthosteric ligands. Separately, induced proximity modalities alter protein function by inducing an interaction between a target protein and an effector protein, like the E3 ligase substrate adapter cereblon (CRBN), which promotes the proteasomal degradation of the target. CRBN ligands that bind at the thalidomide-binding domain have seeded versatile chemical platforms for molecular glue degraders and proteolysis-targeting chimeras (PROTACs). CRBN gains its remarkable inducible substrate scope through conformational shifts that can be mediated by allosteric ligands to alter protein degradation outcomes. We merge the intersection of allostery with induced proximity modalities by examining it first in the context of allosteric pharmacology and second in the context of targeted protein degradation with CRBN, highlighting how lessons learned from allostery with other therapeutic targets could inform emerging opportunities for allosteric modulation of induced proximity events. This intersection of allostery and induced proximity at CRBN conceptually unites two major chemical means of changing protein fate, bringing the potential for highly selective and potent chemical modalities for a greater part of the proteome closer to reality.
SN  - 2374-7943
SN  - 2374-7951
ER  -