8BC7

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

8BC7 の概要

• エントリーDOI: 10.2210/pdb8bc7/pdb
• 分子名称: Cereblon isoform 4, PHE-PHE-GLU-GLN-MET-GLN-QCI, ZINC ION, ... (5 entities in total)
• 機能のキーワード: protein damage, protein ageing, protein chain break, aminoglutarimide, signaling protein
• 由来する生物種: Magnetospirillum gryphiswaldense; 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 42678.41

構造登録者

Heim, C.,Albrecht, R.,Spring, A.K.,Hartmann, M.D. (登録日: 2022-10-15, 公開日: 2023-01-11, 最終更新日: 2024-11-13)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.719 Å)