7LPS

Crystal structure of DDB1-CRBN-ALV1 complex bound to Helios (IKZF2 ZF2)

Summary for 7LPS

• Entry DOI: 10.2210/pdb7lps/pdb
• Descriptor: DNA damage-binding protein 1, Protein cereblon, Zinc finger protein Helios, ... (5 entities in total)
• Functional Keywords: crbn, ddb1, ikzf2, alv, degradation, e3 ligase, ligase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 12
• Total formula weight: 703337.26

Authors

Nowak, R.P.,Fischer, E.S. (deposition date: 2021-02-12, release date: 2021-06-02, Last modification date: 2023-10-18)

Primary citation

Wang, E.S.,Verano, A.L.,Nowak, R.P.,Yuan, J.C.,Donovan, K.A.,Eleuteri, N.A.,Yue, H.,Ngo, K.H.,Lizotte, P.H.,Gokhale, P.C.,Gray, N.S.,Fischer, E.S.
Acute pharmacological degradation of Helios destabilizes regulatory T cells.
Nat.Chem.Biol., 17:711-717, 2021

PubMed Abstract: The zinc-finger transcription factor Helios is critical for maintaining the identity, anergic phenotype and suppressive activity of regulatory T (T) cells. While it is an attractive target to enhance the efficacy of currently approved immunotherapies, no existing approaches can directly modulate Helios activity or abundance. Here, we report the structure-guided development of small molecules that recruit the E3 ubiquitin ligase substrate receptor cereblon to Helios, thereby promoting its degradation. Pharmacological Helios degradation destabilized the anergic phenotype and reduced the suppressive activity of T cells, establishing a route towards Helios-targeting therapeutics. More generally, this study provides a framework for the development of small-molecule degraders for previously unligandable targets by reprogramming E3 ligase substrate specificity.

PubMed: 34035522
DOI: 10.1038/s41589-021-00802-w

Experimental method

X-RAY DIFFRACTION (3.78 Å)