6R0Q

Mutant cereblon isoform 4 from Magnetospirillum gryphiswaldense in complex with thalidomide metabolite alpha-(o-carboxybenzamido)glutarimide

Summary for 6R0Q

• Entry DOI: 10.2210/pdb6r0q/pdb
• Descriptor: Cereblon isoform 4, ALA-ALA-ALA, ALA-ALA-ALA-ALA, ... (6 entities in total)
• Functional Keywords: signaling protein, proteolysis targeting chimera, protac, protein degradation, hydrolysis product
• Biological source: Magnetospirillum gryphiswaldense MSR-1; More
• Total number of polymer chains: 8
• Total formula weight: 57611.00

Authors

Heim, C.,Hartmann, M.D. (deposition date: 2019-03-13, release date: 2019-08-07, Last modification date: 2024-01-24)

Primary citation

Heim, C.,Pliatsika, D.,Mousavizadeh, F.,Bar, K.,Hernandez Alvarez, B.,Giannis, A.,Hartmann, M.D.
De-Novo Design of Cereblon (CRBN) Effectors Guided by Natural Hydrolysis Products of Thalidomide Derivatives.
J.Med.Chem., 62:6615-6629, 2019

PubMed Abstract: Targeted protein degradation via cereblon (CRBN), a substrate receptor of an E3 ubiquitin ligase complex, is an increasingly important strategy in various clinical settings, in which the substrate specificity of CRBN is altered via the binding of small-molecule effectors. To date, such effectors are derived from thalidomide and confer a broad substrate spectrum that is far from being fully characterized. Here, we employed a rational and modular approach to design novel and minimalistic CRBN effectors. In this approach, we took advantage of the binding modes of hydrolyzed metabolites of several thalidomide-derived effectors, which we elucidated via crystallography. These yielded key insights for the optimization of the minimal core binding moiety and its linkage to a chemical moiety that imparts substrate specificity. Based on this scaffold, we present a first active de-novo CRBN effector that is able to degrade the neo-substrate IKZF3 in the cell culture.

PubMed: 31251063
DOI: 10.1021/acs.jmedchem.9b00454

Experimental method

X-RAY DIFFRACTION (1.5 Å)