8BC7

Cereblon isoform 4 from Magnetospirillum gryphiswaldense in complex an aminoglutarimide degron peptide

Summary for 8BC7

• Entry DOI: 10.2210/pdb8bc7/pdb
• Descriptor: Cereblon isoform 4, PHE-PHE-GLU-GLN-MET-GLN-QCI, ZINC ION, ... (5 entities in total)
• Functional Keywords: protein damage, protein ageing, protein chain break, aminoglutarimide, signaling protein
• Biological source: Magnetospirillum gryphiswaldense; More
• Total number of polymer chains: 4
• Total formula weight: 42678.41

Authors

Heim, C.,Albrecht, R.,Spring, A.K.,Hartmann, M.D. (deposition date: 2022-10-15, release date: 2023-01-11, Last modification date: 2024-11-13)

Primary citation

Heim, C.,Spring, A.K.,Kirchgassner, S.,Schwarzer, D.,Hartmann, M.D.
Identification and structural basis of C-terminal cyclic imides as natural degrons for cereblon.
Biochem.Biophys.Res.Commun., 637:66-72, 2022

PubMed Abstract: Cereblon (CRBN) is a ubiquitously expressed E3 ligase substrate receptor and a key player in pharmaceutical targeted protein degradation. Despite substantial insight gained into its chemical ligand space that is exploited in small-molecule protein degraders, its cellular role and native mechanism of substrate recognition remained elusive so far. In this communication, we report the discovery of C-terminal aspartimide and aminoglutarimide residues as natural degron motifs that are recognized by CRBN with high specificity. These C-terminal cyclic imides are known to form in ageing proteins as a result of spontaneous chain breaks after an attack of an asparagine or glutamine side chain amide on the adjacent peptide bond, and thereby mark potentially malfunctional protein fragments. In crystal structures, we uncover that these C-terminal cyclic imides are bound in the same fashion as small-molecule CRBN modulators, and that the residues preceding the cyclic terminus contribute to the interaction with a sequence-unspecific backbone hydrogen bonding pattern with strictly conserved residues in CRBN. We postulate that C-terminal aspartimide and aminoglutarimide residues resulting from chain breaks are largely underappreciated protein damages and represent the native degrons of CRBN.

PubMed: 36375252
DOI: 10.1016/j.bbrc.2022.11.001

Experimental method

X-RAY DIFFRACTION (1.719 Å)