9qfs
Structure of CHIP E3 ubiquitin ligase TPR domain in complex with compound 8.
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 PubMedSTIP1 homology and U-box containing protein 1 (STUB1), also known as the C-terminus of Hsc70-interacting protein (CHIP), is an E3 ligase that plays a crucial role in removal of misfolded proteins via Hsc70. A DEL screen was run against CHIP to identify small-molecule binders. Two hits were identified that were confirmed by biochemical and biophysical techniques, including 2D NMR. X-ray crystal structures were obtained, which revealed binding to the peptide binding site. Fragment-based deconstruction indicated that hit 2 was a suitable starting point for optimization. During the optimization, an unexpected rearrangement of an oxadiazole from an array hit led to the exploration of an amide vector. This resulted in the discovery of compound 5, which is the most potent small-molecule ligand for CHIP identified to date and a suitable starting point for further optimization into a tool molecule or PROTAC warhead. Discovery of Small-Molecule Ligands for the E3 Ligase STUB1/CHIP from a DNA-Encoded Library Screen.,Lucas SCC, Milbradt AG, Breed J, De Genst E, Jackson A, Solovyeva A, Ackroyd B, Bauer MR, Liu J, Longmire D, Petrovic D, Rivers EL, Stubbs C, Winlow P, Bazzaz S, Dickson P, Gikunju D, Guie MA, Guilinger JP, Hupp CD, Jetson R, Keefe AD, Nugai K, Yeoman JTS, Zhang Y, Feng X, Yu D, Phillips C ACS Med Chem Lett. 2025 Aug 5;16(8):1445-1451. doi: , 10.1021/acsmedchemlett.5c00361. eCollection 2025 Aug 14. PMID:40832528[9] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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