5OHB

Cereblon isoform 4 from Magnetospirillum gryphiswaldense in complex with Piperidin-2-one (Valerolactam)

Summary for 5OHB

• Entry DOI: 10.2210/pdb5ohb/pdb
• Descriptor: Cereblon isoform 4, ZINC ION, piperidin-2-one, ... (4 entities in total)
• Functional Keywords: teratogenicity, protein degradation, substrate recognition, ubiquitin ligase, unknown function
• Biological source: Magnetospirillum gryphiswaldense MSR-1
• Total number of polymer chains: 3
• Total formula weight: 41604.35

Authors

Boichenko, I.,Albrecht, R.,Lupas, A.N.,Hernandez Alvarez, B.,Hartmann, M.D. (deposition date: 2017-07-14, release date: 2018-10-10, Last modification date: 2024-01-17)

Primary citation

Boichenko, I.,Bar, K.,Deiss, S.,Heim, C.,Albrecht, R.,Lupas, A.N.,Hernandez Alvarez, B.,Hartmann, M.D.
Chemical Ligand Space of Cereblon.
Acs Omega, 3:11163-11171, 2018

PubMed Abstract: The protein cereblon serves as a substrate receptor of a ubiquitin ligase complex that can be tuned toward different target proteins by cereblon-binding agents. This approach to targeted protein degradation is exploited in different clinical settings and has sparked the development of a growing number of thalidomide derivatives. Here, we probe the chemical space of cereblon binding beyond such derivatives and work out a simple set of chemical requirements, delineating the metaclass of cereblon effectors. We report co-crystal structures for a diverse set of compounds, including commonly used pharmaceuticals, but also find that already minimalistic cereblon-binding moieties might exert teratogenic effects in zebrafish. Our results may guide the design of a post-thalidomide generation of therapeutic cereblon effectors and provide a framework for the circumvention of unintended cereblon binding by negative design for future pharmaceuticals.

PubMed: 31459225
DOI: 10.1021/acsomega.8b00959

Experimental method

X-RAY DIFFRACTION (1.7 Å)