8TZX

Ternary complex structure of Cereblon-DDB1 bound to WIZ(ZF7) and the molecular glue dWIZ-1

Summary for 8TZX

• Entry DOI: 10.2210/pdb8tzx/pdb
• Descriptor: Protein cereblon, DNA damage-binding protein 1, Protein Wiz, ... (8 entities in total)
• Functional Keywords: complex, glue, ligase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 280743.67

Authors

Clifton, M.C.,Ma, X.,Ornelas, E. (deposition date: 2023-08-28, release date: 2024-07-10, Last modification date: 2024-10-23)

Primary citation

Ting, P.Y.,Borikar, S.,Kerrigan, J.R.,Thomsen, N.M.,Aghania, E.,Hinman, A.E.,Reyes, A.,Pizzato, N.,Fodor, B.D.,Wu, F.,Belew, M.S.,Mao, X.,Wang, J.,Chitnis, S.,Niu, W.,Hachey, A.,Cobb, J.S.,Savage, N.A.,Burke, A.,Paulk, J.,Dovala, D.,Lin, J.,Clifton, M.C.,Ornelas, E.,Ma, X.,Ware, N.F.,Sanchez, C.C.,Taraszka, J.,Terranova, R.,Knehr, J.,Altorfer, M.,Barnes, S.W.,Beckwith, R.E.J.,Solomon, J.M.,Dales, N.A.,Patterson, A.W.,Wagner, J.,Bouwmeester, T.,Dranoff, G.,Stevenson, S.C.,Bradner, J.E.
A molecular glue degrader of the WIZ transcription factor for fetal hemoglobin induction.
Science, 385:91-99, 2024

PubMed Abstract: Sickle cell disease (SCD) is a prevalent, life-threatening condition attributable to a heritable mutation in β-hemoglobin. Therapeutic induction of fetal hemoglobin (HbF) can ameliorate disease complications and has been intently pursued. However, safe and effective small-molecule inducers of HbF remain elusive. We report the discovery of dWIZ-1 and dWIZ-2, molecular glue degraders of the WIZ transcription factor that robustly induce HbF in erythroblasts. Phenotypic screening of a cereblon (CRBN)-biased chemical library revealed WIZ as a previously unknown repressor of HbF. WIZ degradation is mediated by recruitment of WIZ(ZF7) to CRBN by dWIZ-1, as resolved by crystallography of the ternary complex. Pharmacological degradation of WIZ was well tolerated and induced HbF in humanized mice and cynomolgus monkeys. These findings establish WIZ degradation as a globally accessible therapeutic strategy for SCD.

PubMed: 38963839
DOI: 10.1126/science.adk6129

Experimental method

X-RAY DIFFRACTION (3.15 Å)