7TB1
Crystal structure of STUB1 with a macrocyclic peptide
Summary for 7TB1
| Entry DOI | 10.2210/pdb7tb1/pdb |
| Descriptor | E3 ubiquitin-protein ligase CHIP, ALA-CYS-SER-SER-ILE-TRP-CYS-PRO-ASP-GLY, 1,3-bis(sulfanyl)propan-2-one, ... (4 entities in total) |
| Functional Keywords | e3 ligase, carboxy-terminus of hsp70-interacting protein, transferase |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 33906.45 |
| Authors | Bahmanjah, S.,Klein, D.J. (deposition date: 2021-12-21, release date: 2022-07-27, Last modification date: 2024-11-06) |
| Primary citation | Ng, S.,Brueckner, A.C.,Bahmanjah, S.,Deng, Q.,Johnston, J.M.,Ge, L.,Duggal, R.,Habulihaz, B.,Barlock, B.,Ha, S.,Sadruddin, A.,Yeo, C.,Strickland, C.,Peier, A.,Henry, B.,Sherer, E.C.,Partridge, A.W. Discovery and Structure-Based Design of Macrocyclic Peptides Targeting STUB1. J.Med.Chem., 2022 Cited by PubMed Abstract: Recent evidence suggests that deletion of STUB1─a pivotal negative regulator of interferon-γ sensing─may potentially clear malignant cells. However, current studies rely primarily on genetic approaches, as pharmacological inhibitors of STUB1 are lacking. Identifying a tool compound will be a step toward validating the target in a broader therapeutic sense. Herein, screening more than a billion macrocyclic peptides resulted in STUB1 binders, which were further optimized by a structure-enabled design. The strategy to replace the macrocyclic peptides' hydrophilic and solvent-exposed region with a hydrophobic scaffold improved cellular permeability while maintaining the binding conformation. Further substitution of the permeability-limiting terminal aspartic acid with a tetrazole bioisostere retained the binding to a certain extent while improving permeability, suggesting a path forward. Although not optimal for cellular study, the current lead provides a valuable template for further development into selective tool compounds for STUB1 to enable target validation. PubMed: 35853179DOI: 10.1021/acs.jmedchem.2c00406 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.785 Å) |
Structure validation
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