Chemical Ligand Space of Cereblon

Boichenko, I; Bär, K; Deiss, S; Heim, C; Albrecht, R; Lupas, AN; Hernandez Alvarez, B; Hartmann, MD

doi:10.1021/acsomega.8b00959

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Chemical Ligand Space of Cereblon

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Boichenko, I
Department Protein Evolution, Max Planck Institute for Developmental Biology, Max Planck Society;
Conservation of Protein Structure and Function Group, Department Protein Evolution, Max Planck Institute for Developmental Biology, Max Planck Society;

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Bär, K
Department Protein Evolution, Max Planck Institute for Developmental Biology, Max Planck Society;

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Deiss, S
Department Protein Evolution, Max Planck Institute for Developmental Biology, Max Planck Society;
Conservation of Protein Structure and Function Group, Department Protein Evolution, Max Planck Institute for Developmental Biology, Max Planck Society;

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Heim, C
Department Protein Evolution, Max Planck Institute for Developmental Biology, Max Planck Society;
Molecular Recognition and Catalysis Group, Department Protein Evolution, Max Planck Institute for Developmental Biology, Max Planck Society;

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Albrecht, R
Department Protein Evolution, Max Planck Institute for Developmental Biology, Max Planck Society;
Molecular Recognition and Catalysis Group, Department Protein Evolution, Max Planck Institute for Developmental Biology, Max Planck Society;

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Lupas, AN
Department Protein Evolution, Max Planck Institute for Developmental Biology, Max Planck Society;

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Hernandez Alvarez, B
Department Protein Evolution, Max Planck Institute for Developmental Biology, Max Planck Society;
Conservation of Protein Structure and Function Group, Department Protein Evolution, Max Planck Institute for Developmental Biology, Max Planck Society;

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Hartmann, MD
Department Protein Evolution, Max Planck Institute for Developmental Biology, Max Planck Society;
Molecular Recognition and Catalysis Group, Department Protein Evolution, Max Planck Institute for Developmental Biology, Max Planck Society;

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引用

Boichenko, I., Bär, K., Deiss, S., Heim, C., Albrecht, R., Lupas, A., Hernandez Alvarez, B., & Hartmann, M. (2018). Chemical Ligand Space of Cereblon. ACS Omega, 3(9), 11163-11171. doi:10.1021/acsomega.8b00959.

引用: https://hdl.handle.net/21.11116/0000-000A-6681-1

要旨

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.