8F1F

Structure of K48-linked tri-ubiquitin in complex with cyclic peptide

8F1F の概要

• エントリーDOI: 10.2210/pdb8f1f/pdb
• 分子名称: Ubiquitin, Non-proteinogenic cyclic peptide (inhibitor), GLYCEROL, ... (7 entities in total)
• 機能のキーワード: complex, therapeutic peptide, lys48-linked polyubiquitin, macrocyclic peptide, inhibitor of ubiquitin signaling, signaling protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 55291.38

構造登録者

Lubkowski, J.,Fushman, D.,Lemma, B. (登録日: 2022-11-05, 公開日: 2023-11-01, 最終更新日: 2024-11-20)

主引用文献

Lemma, B.,Zhang, D.,Vamisetti, G.B.,Wentz, B.G.,Suga, H.,Brik, A.,Lubkowski, J.,Fushman, D.
Mechanism of selective recognition of Lys48-linked polyubiquitin by macrocyclic peptide inhibitors of proteasomal degradation.
Nat Commun, 14:7212-7212, 2023

PubMed Abstract: Post-translational modification of proteins with polyubiquitin chains is a critical cellular signaling mechanism in eukaryotes with implications in various cellular states and processes. Unregulated ubiquitin-mediated protein degradation can be detrimental to cellular homeostasis, causing numerous diseases including cancers. Recently, macrocyclic peptides were developed that selectively target long Lysine-48-linked polyubiquitin chains (tetra-ubiquitin) to inhibit ubiquitin-proteasome system, leading to attenuation of tumor growth in vivo. However, structural determinants of the chain length and linkage selectivity by these cyclic peptides remained unclear. Here, we uncover the mechanism underlying cyclic peptide's affinity and binding selectivity by combining X-ray crystallography, solution NMR, and biochemical studies. We found that the peptide engages three consecutive ubiquitins that form a ring around the peptide and determined requirements for preferential selection of a specific trimer moiety in longer polyubiquitin chains. The structural insights gained from this work will guide the development of next-generation cyclic peptides with enhanced anti-cancer activity.

PubMed: 37938554
DOI: 10.1038/s41467-023-43025-4

実験手法

X-RAY DIFFRACTION (1.85 Å)