9NGT

Crystal structure of CRBN-DDB1 and FPFT-2216 in complex with mTOR

This is a non-PDB format compatible entry.

Summary for 9NGT

• Entry DOI: 10.2210/pdb9ngt/pdb
• Descriptor: DNA damage-binding protein 1, Protein cereblon, Serine/threonine-protein kinase mTOR, ... (5 entities in total)
• Functional Keywords: ternary complex, molecular glue degrader, neosubstrate, dna binding protein-transferase complex, dna binding protein/transferase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 189862.36

Authors

Petzold, G.,Trenh, P.,Bunker, R.D.,Tsai, J.H.C. (deposition date: 2025-02-22, release date: 2025-07-09, Last modification date: 2025-07-16)

Primary citation

Petzold, G.,Gainza, P.,Annunziato, S.,Lamberto, I.,Trenh, P.,McAllister, L.A.,DeMarco, B.,Schwander, L.,Bunker, R.D.,Zlotosch, M.,SriRamaratnam, R.,Gilberto, S.,Langousis, G.,Donckele, E.J.,Quan, C.,Strande, V.,De Donatis, G.M.,Alabi, S.B.,Alers, J.,Matysik, M.,Staehly, C.,Dubois, A.,Osmont, A.,Garskovas, M.,Lyon, D.,Wiedmer, L.,Oleinikovas, V.,Lieberherr, R.,Rubin, N.T.,Lam, D.T.,Lucas, X.,Liardo, E.,Widlund, N.I.,Ritzen, A.,Caceres, R.M.,Vigil, D.,Tsai, J.,Wallace, O.,Peluso, M.,Sadok, A.,Tiedt, R.,Paterson, A.M.,Zarayskiy, V.,Fasching, B.,Bonenfant, D.,Warmuth, M.,Castle, J.C.,Townson, S.A.
Mining the CRBN target space redefines rules for molecular glue-induced neosubstrate recognition.
Science, 389:eadt6736-eadt6736, 2025

PubMed Abstract: The CRL4 E3 ubiquitin ligase is the target of molecular glue degrader compounds that reprogram ligase specificity to induce the degradation of clinically relevant neosubstrate proteins. Known cereblon (CRBN) neosubstrates share a generalizable β-hairpin G-loop recognition motif that allows for the systematic exploration of the CRBN target space. Computational mining approaches using structure- and surface-based matchmaking algorithms predict more than 1600 CRBN-compatible G-loop proteins across the human proteome, including the newly discovered helical G-loop motif, and identify the noncanonical neosubstrate binding mode of VAV1 that engages CRBN through a molecular surface mimicry mechanism. This work broadens the CRBN target space, redefines rules for neosubstrate recognition, and establishes a platform for the elimination of challenging drug targets by repurposing CRL4 through next-generation molecular glue degraders.

PubMed: 40608931
DOI: 10.1126/science.adt6736

Experimental method

X-RAY DIFFRACTION (2.95 Å)