9T95
Crystal structure of beta-TrCP bound by diphosphorylated NRF2 degron peptide.
Summary for 9T95
| Entry DOI | 10.2210/pdb9t95/pdb |
| Descriptor | F-box/WD repeat-containing protein 1A, Nuclear factor erythroid 2-related factor 2 (3 entities in total) |
| Functional Keywords | beta-trcp, e3 ligase, phosphodegron, nrf2, ligase |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 2 |
| Total formula weight | 43198.86 |
| Authors | Collie, G.W. (deposition date: 2025-11-13, release date: 2026-04-08, Last modification date: 2026-04-29) |
| Primary citation | O Donovan, D.H.,Winter-Holt, J.,Collie, G.W.,Cuomo, M.E.,McGarry, D.J.,Fox, M.,Alex Seong, B.K.,Grazini, U.,Barton, P.,Longmire, D.,Lister, A.,Xu, Y.,Mak, H.,Barrey, E.J.,Acebron-Garcia-de-Eulate, M.,Richter, M.,Peter, N.,Couturier, M.,Gutierrez, G.J.,Guilbert, R.,Lee, W.,Lochhead, P.A.,Argyrou, A. Targeting the Interaction of NRF2 and beta-TrCP with Molecular Glues. Acs Chem.Biol., 21:635-642, 2026 Cited by PubMed Abstract: Inhibiting the oncogenic driver NRF2 in non-small cell lung cancer (NSCLC) represents a promising yet challenging clinical opportunity. Small molecules that enhance the NRF2:β-TrCP interaction ("molecular glues") could hold therapeutic potential by promoting the ubiquitination and proteasomal degradation of NRF2. NRX-252114 is a molecular glue previously reported to promote the interaction between β-catenin and β-TrCP. We now find that NRX-252114 can also enhance the association between β-TrCP and NRF2 phosphodegron peptides. To leverage this novel interaction for the development of NRF2:β-TrCP molecular glues, we synthesized and evaluated a library of chemical analogues, guided by homology modeling and subsequently by X-ray crystallography. Surprisingly, structural elucidation of the NRF2:β-TrCP complex revealed occlusion of the presumed molecular glue binding pocket. This mechanistic insight explains the limited affinity enhancement for analogues of NRX-252114, and provides a structural rationale for the lack of NRF2 degradation in cells. Our findings broaden the scope of β-TrCP-targeted molecular glues, demonstrate that NRF2 is "glueable" at the peptide level, and provide mechanistic guidance for future efforts to target the pharmacologically elusive NRF2 pathway in cancer. PubMed: 41910202DOI: 10.1021/acschembio.5c01006 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.145 Å) |
Structure validation
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