8r5c
From Proteopedia
Crystal structure of human TRIM7 PRYSPRY domain bound to (2-(1-oxoisoindolin-2-yl)-3-phenylpropanoyl)-L-glutamine
Structural highlights
FunctionTRIM7_HUMAN E3 ubiquitin-protein ligase. Mediates 'Lys-63'-linked polyubiquitination and stabilization of the JUN coactivator RNF187 in response to growth factor signaling via the MEK/ERK pathway, thereby regulating JUN transactivation and cellular proliferation (PubMed:25851810). Promotes the TLR4-mediated signaling activation through its E3 ligase domain leading to production of proinflammatory cytokines and type I interferon (By similarity). Plays also a negative role in the regulation of exogenous cytosolic DNA virus-triggered immune response. Mechanistically, enhances the 'Lys-48'-linked ubiquitination of STING1 leading to its proteasome-dependent degradation (PubMed:32126128).[UniProtKB:Q923T7][1] [2] (Microbial infection) Promotes Zika virus replication by mediating envelope protein E ubiquitination.[3] Publication Abstract from PubMedTRIM7 is a ubiquitin E3 ligase with key regulatory functions, mediating viral infection, tumor biology, innate immunity, and cellular processes, such as autophagy and ferroptosis. It contains a PRYSPRY domain that specifically recognizes degron sequences containing C-terminal glutamine. Ligands that bind to the TRIM7 PRYSPRY domain may have applications in the treatment of viral infections, as modulators of inflammation, and in the design of a new class of PROTACs (PROteolysis TArgeting Chimeras) that mediate the selective degradation of therapeutically relevant proteins (POIs). Here, we developed an assay toolbox for the comprehensive evaluation of TRIM7 ligands. Using TRIM7 degron sequences together with a structure-based design, we developed the first series of peptidomimetic ligands with low micromolar affinity. The terminal carboxylate moiety was required for ligand activity but prevented cell penetration. A prodrug strategy using an ethyl ester resulted in enhanced permeability, which was evaluated using confocal imaging. A C-Degron Structure-Based Approach for the Development of Ligands Targeting the E3 Ligase TRIM7.,Munoz Sosa CJ, Lenz C, Hamann A, Farges F, Dopfer J, Kramer A, Cherkashyna V, Tarnovskiy A, Moroz YS, Proschak E, Nemec V, Muller S, Saxena K, Knapp S ACS Chem Biol. 2024 Jul 19;19(7):1638-1647. doi: 10.1021/acschembio.4c00301. Epub , 2024 Jun 27. PMID:38934237[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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