8ZCS

Crystal structure of the MBP-MCL1 complex with highly selective and potent Cyclic peptide inhibitor

Summary for 8ZCS

• Entry DOI: 10.2210/pdb8zcs/pdb
• Related PRD ID: PRD_900010 PRD_900030
• Descriptor: Maltose/maltodextrin-binding periplasmic protein,Induced myeloid leukemia cell differentiation protein Mcl-1, TYR-LEU-LEU-PHE-TRP-ARG-ASP-GLU-LEU-ILE-LEU-LEU-CCJ-NH2, alpha-D-glucopyranose-(1-4)-alpha-D-glucopyranose-(1-4)-alpha-D-glucopyranose-(1-4)-alpha-D-glucopyranose, ... (5 entities in total)
• Functional Keywords: inhibitor, molecular glue, cyclic peptide, apoptosis
• Biological source: Escherichia coli K-12; More
• Total number of polymer chains: 3
• Total formula weight: 118537.84

Authors

Li, F.W. (deposition date: 2024-04-30, release date: 2025-03-19, Last modification date: 2025-04-02)

Primary citation

Li, F.,Zhang, M.,Liu, C.,Cheng, J.,Yang, Y.,Peng, X.,Li, Z.,Cai, W.,Yu, H.,Wu, J.,Guo, Y.,Geng, H.,Fa, Y.,Zhang, Y.,Wu, D.,Yin, Y.
De novo discovery of a molecular glue-like macrocyclic peptide that induces MCL1 homodimerization.
Proc.Natl.Acad.Sci.USA, 122:e2426006122-e2426006122, 2025

PubMed Abstract: Macrocyclic peptides have emerged as promising drug candidates, filling the gap between small molecules and large biomolecules in drug discovery. The antiapoptotic protein myeloid cell leukemia 1 (MCL1) is crucial for numerous cancers, yet it presents challenges for selective targeting by traditional inhibitors. In this study, we identified a macrocyclic peptide, 5L1, that strongly binds to MCL1, with a dissociation constant () of 7.1 nM. This peptide shows the potential to specifically inhibit the function of MCL1, and demonstrates effective antitumor activity against several blood tumor cell lines with the half maximal inhibitory concentration (IC) values for cell-penetrating peptide-conjugated 5L1 in the range of 0.6 to 3 μM. Structural analysis revealed that it functions similarly to molecular glue, capable of binding to two MCL1 molecules simultaneously and inducing their homodimerization. This unique mechanism of action distinguishes it from traditional small-molecule MCL1 inhibitors, underscoring the potential of macrocyclic peptides functioning as molecular glues. Moreover, it inspires the development of highly selective inhibitors targeting MCL1 and other related targets with this glue-like mechanism.

PubMed: 40131955
DOI: 10.1073/pnas.2426006122

Experimental method

X-RAY DIFFRACTION (2.79 Å)