bims-cutpro 2026-01-25 papers

on Cullin targeted protein degradation

Issue of 2026–01–25
two papers selected by
James M. Krieger, Francis Crick Institute

Identification of an allosteric site on the E3 ligase adapter cereblon.
Cereblon induces G3BP2 neosubstrate degradation using molecular surface mimicry.

Nature. 2026 Jan 21.

Identification of an allosteric site on the E3 ligase adapter cereblon.

Vanessa N Dippon, Zeba Rizvi, Anthony E Choudhry, Chun-Wa Chung, Ibrahim F Alkuraya, Wenqing Xu, Xavier B Tao, Anthony J Jurewicz, Jessica L Schneck, Wenqian Chen, Nicole M Curnutt, Farah Kabir, Kwok-Ho Chan, Markus A Queisser, Caterina Musetti, Han Dai, Gabriel C Lander, Andrew B Benowitz, Christina M Woo.

Cereblon (CRBN) is the target of thalidomide derivatives1 that achieve therapeutic efficacy against some haematologic neoplasias2-4 by recruiting neosubstrates for degradation5-7. Despite the intense investigation of orthosteric thalidomide derivatives, little is known about alternate binding sites on CRBN. Here we report an evolutionarily conserved cryptic allosteric binding site on CRBN. Small-molecule SB-405483 binds the allosteric site to cooperatively enhance the binding of orthosteric ligands and alter their neosubstrate degradation profiles. A survey of over 100 orthosteric ligands and their degradation targets reveals trends in the classes of compounds and neosubstrates in which degradation outcomes are enhanced or inhibited by SB-405483. Structural investigations provide a mechanistic basis for the effects of the allosteric ligand by shifting the conformational distribution of CRBNopen to a novel CRBNint and increasing the CRBNclosed state. The discovery of a cryptic allosteric binding site on CRBN that alters the functional effects of orthosteric ligands opens new directions with broad implications for improving the selectivity and efficacy of CRBN therapeutics.

DOI: https://doi.org/10.1038/s41586-025-09994-w
Nat Struct Mol Biol. 2026 Jan 20.

Cereblon induces G3BP2 neosubstrate degradation using molecular surface mimicry.

Stefano Annunziato, Chao Quan, Etienne J Donckele, Ilaria Lamberto, Richard D Bunker, Mary Zlotosch, Laura Schwander, Anastasia Murthy, Lars Wiedmer, Camille Staehly, Michelle Matysik, Samuel Gilberto, Despina Kapsitidou, Daric Wible, Gian Marco De Donatis, Peter Trenh, Rohitha SriRamaratnam, Vaik Strande, Raphael Lieberherr, David Lyon, Danielle Steiner, Joao Silva, Reinaldo Almeida, Elena Dolgikh, Bradley DeMarco, Jennifer Tsai, Amine Sadok, Vladislav Zarayskiy, Magnus Walter, Ralph Tiedt, Kevin J Lumb, Debora Bonenfant, Bernhard Fasching, John C Castle, Sharon A Townson, Pablo Gainza, Georg Petzold.

Molecular glue degraders (MGDs) are small-molecule compounds that divert E3 ligases to degrade nonnatural substrates called neosubstrates. Clinically effective MGDs bind cereblon (CRBN), a substrate receptor of the Cullin 4-RING E3 ubiquitin ligase (CRL4CRBN), and recruit neosubstrates to an MGD-induced neosurface on the CRBN CULT domain through molecular mimicry of a natural CRBN degron. Here, we identify G3BP2 (Ras-GAP SH3 domain-binding protein 2), a neosubstrate that bypasses canonical interactions with CRBN by engaging an unconventional binding site on the CRBN LON domain. The ternary complex interface does not resemble known interactions with CRBN. Instead, CRBN leverages a preexisting protein-protein interaction (PPI) hotspot on the target protein by mimicking an endogenous binding partner of G3BP2. Our findings suggest that composite neosurfaces that mimic and stabilize the footprint of natural PPIs (in short, 'glueprints') could become a viable strategy for the rational expansion of the MGD target repertoire.

DOI: https://doi.org/10.1038/s41594-025-01738-8