Cereblon neo-substrate binding mimics the recognition of the cyclic imide degron

Heim, C; Spring, A-K; Kirchgäßner, S; Schwarzer, D; Hartmann, MD

doi:10.1016/j.bbrc.2023.01.051

Item

ITEM ACTIONSEXPORT

Add to Basket

Local TagsRelease HistoryDetailsSummary

Released

Journal Article

Cereblon neo-substrate binding mimics the recognition of the cyclic imide degron

MPS-Authors

/persons/resource/persons271516

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

/persons/resource/persons282953

Spring, A-K
Molecular Recognition and Catalysis Group, Department Protein Evolution, Max Planck Institute for Biology Tübingen, Max Planck Society;
Department Protein Evolution, Max Planck Institute for Biology Tübingen, Max Planck Society;

/persons/resource/persons271510

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

External Resource

No external resources are shared

Fulltext (restricted access)

There are currently no full texts shared for your IP range.

Fulltext (public)

There are no public fulltexts stored in PuRe

Supplementary Material (public)

There is no public supplementary material available

Citation

Heim, C., Spring, A.-K., Kirchgäßner, S., Schwarzer, D., & Hartmann, M. (2023). Cereblon neo-substrate binding mimics the recognition of the cyclic imide degron. Biochemical and Biophysical Research Communications, 646, 30-35. doi:10.1016/j.bbrc.2023.01.051.

Cite as: https://hdl.handle.net/21.11116/0000-000C-7AD6-A

Abstract

In targeted protein degradation, immunomodulatory drugs (IMiDs) or cereblon (CRBN) E3 ligase modulatory drugs (CELMoDs) recruit neo-substrate proteins to the E3 ubiquitin ligase receptor CRBN for ubiquitination and subsequent proteasomal degradation. While the structural basis of this mechanism is generally understood, we have only recently described the recognition mode of the natural CRBN degron. In this communication, we reveal that the IMiD- or CELMoD-mediated binding of neo-substrates closely mimics the recognition of natural degrons. In crystal structures, we identify a conserved binding mode for natural degron peptides with an elaborate hydrogen bonding network involving the backbone of each of the six C-terminal degron residues, without the involvement of side chains. In a structural comparison, we show that neo-substrates recruited by IMiDs or CELMoDs emulate every single hydrogen bond of this network and thereby explain the origins of the largely sequence-independent recognition of neo-substrates. Our results imply that the V388I substitution in CRBN does not impair natural degron recognition and complete the structural basis for the rational design of CRBN effectors.