7tb1
From Proteopedia
Crystal structure of STUB1 with a macrocyclic peptide
Structural highlights
DiseaseCHIP_HUMAN Cerebellar ataxia - hypogonadism. The disease is caused by mutations affecting the gene represented in this entry. FunctionCHIP_HUMAN E3 ubiquitin-protein ligase which targets misfolded chaperone substrates towards proteasomal degradation. Collaborates with ATXN3 in the degradation of misfolded chaperone substrates: ATXN3 restricting the length of ubiquitin chain attached to STUB1/CHIP substrates and preventing further chain extension. Ubiquitinates NOS1 in concert with Hsp70 and Hsp40. Modulates the activity of several chaperone complexes, including Hsp70, Hsc70 and Hsp90. Mediates transfer of non-canonical short ubiquitin chains to HSPA8 that have no effect on HSPA8 degradation. Mediates polyubiquitination of DNA polymerase beta (POLB) at 'Lys-41', 'Lys-61' and 'Lys-81', thereby playing a role in base-excision repair: catalyzes polyubiquitination by amplifying the HUWE1/ARF-BP1-dependent monoubiquitination and leading to POLB-degradation by the proteasome. Mediates polyubiquitination of CYP3A4. Ubiquitinates EPHA2 and may regulate the receptor stability and activity through proteasomal degradation.[1] [2] [3] [4] [5] [6] [7] [8] Publication Abstract from PubMedRecent evidence suggests that deletion of STUB1 horizontal line a pivotal negative regulator of interferon-gamma sensing horizontal line 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 in silico 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. Discovery and Structure-Based Design of Macrocyclic Peptides Targeting STUB1.,Ng S, Brueckner AC, Bahmanjah S, Deng Q, Johnston JM, Ge L, Duggal R, Habulihaz B, Barlock B, Ha S, Sadruddin A, Yeo C, Strickland C, Peier A, Henry B, Sherer EC, Partridge AW J Med Chem. 2022 Jul 19. doi: 10.1021/acs.jmedchem.2c00406. PMID:35853179[9] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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