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Molecular glue CELMoD compounds are allosteric regulators of cereblon conformation

View ORCID ProfileEdmond R. Watson, View ORCID ProfileScott J. Novick, View ORCID ProfileMary E. Matyskiela, View ORCID ProfilePhilip P. Chamberlain, View ORCID ProfileAndres Hernandez de la Peña, View ORCID ProfileJin-Yi Zhu, Eileen Tran, View ORCID ProfilePatrick R. Griffin, View ORCID ProfileIngrid E. Wertz, View ORCID ProfileGabriel C. Lander
doi: https://doi.org/10.1101/2022.07.02.498551
Edmond R. Watson
1Department of Integrative Structural and Computational Biology, Scripps Research, La Jolla, CA 92037
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Scott J. Novick
2Department of Molecular Medicine, Scripps Research, Jupiter, FL 33458
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Mary E. Matyskiela
3Bristol-Myers Squibb, San Diego, CA 92121
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Philip P. Chamberlain
3Bristol-Myers Squibb, San Diego, CA 92121
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Andres Hernandez de la Peña
3Bristol-Myers Squibb, San Diego, CA 92121
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Jin-Yi Zhu
3Bristol-Myers Squibb, San Diego, CA 92121
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Eileen Tran
3Bristol-Myers Squibb, San Diego, CA 92121
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Patrick R. Griffin
2Department of Molecular Medicine, Scripps Research, Jupiter, FL 33458
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Ingrid E. Wertz
3Bristol-Myers Squibb, San Diego, CA 92121
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Gabriel C. Lander
1Department of Integrative Structural and Computational Biology, Scripps Research, La Jolla, CA 92037
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  • For correspondence: glander@scripps.edu
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Abstract

Cereblon (CRBN) is an ubiquitin ligase (E3) adaptor protein co-opted by CRBN E3 Ligase Modulatory Drugs (CELMoD) agents that target therapeutically-relevant proteins for degradation. Prior crystallographic studies defined the drug-binding site within CRBN’s Thalidomide Binding Domain (TBD), but the allostery of drug-induced neosubstrate binding remains unclear. We therefore performed cryo-EM analyses of the DDB1∼CRBN apo-complex, and compared these structures with DDB1∼CRBN in the presence of CELMoD compounds alone and complexed with neosubstrates. Association of CELMoD compounds to the TBD is necessary and sufficient for triggering CRBN allosteric rearrangement from an “open” conformation to the canonical “closed” conformation. Importantly, the neosubstrate Ikaros only stably associates with the closed CRBN conformation, illustrating the importance of allostery for CELMoD compound efficacy, and informing structure-guided design strategies to improve therapeutic efficacy.

Competing Interest Statement

M. E. Matyskiela, P. P. Chamberlain, A. H. de la Pena, J. Zhu, E. Tran, I. E. Wertz are or were employees of Bristol Myers Squibb and have received Bristol Myers Squibb stock.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted July 03, 2022.
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Molecular glue CELMoD compounds are allosteric regulators of cereblon conformation
Edmond R. Watson, Scott J. Novick, Mary E. Matyskiela, Philip P. Chamberlain, Andres Hernandez de la Peña, Jin-Yi Zhu, Eileen Tran, Patrick R. Griffin, Ingrid E. Wertz, Gabriel C. Lander
bioRxiv 2022.07.02.498551; doi: https://doi.org/10.1101/2022.07.02.498551
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Molecular glue CELMoD compounds are allosteric regulators of cereblon conformation
Edmond R. Watson, Scott J. Novick, Mary E. Matyskiela, Philip P. Chamberlain, Andres Hernandez de la Peña, Jin-Yi Zhu, Eileen Tran, Patrick R. Griffin, Ingrid E. Wertz, Gabriel C. Lander
bioRxiv 2022.07.02.498551; doi: https://doi.org/10.1101/2022.07.02.498551

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