8F1F

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

Summary for 8F1F

• Entry DOI: 10.2210/pdb8f1f/pdb
• Descriptor: Ubiquitin, Non-proteinogenic cyclic peptide (inhibitor), GLYCEROL, ... (7 entities in total)
• Functional Keywords: complex, therapeutic peptide, lys48-linked polyubiquitin, macrocyclic peptide, inhibitor of ubiquitin signaling, signaling protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 8
• Total formula weight: 55291.38

Authors

Lubkowski, J.,Fushman, D.,Lemma, B. (deposition date: 2022-11-05, release date: 2023-11-01, Last modification date: 2024-11-20)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.85 Å)