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Ubiquitin E3 ligase–target protein interface

Molecular classification
Enzyme (E3 ubiquitin ligase), Protein–protein interface, Other (substrate recognition domain), Not a single molecule; classification depends on context (E3s: RING, HECT, RBR/RING-in-between-RING families; substrate as target protein)
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Overview

The **E3 ligase–target protein interface** is the region where an **E3 ubiquitin ligase enzyme** physically interacts with a specific substrate protein to catalyze the transfer of ubiquitin, marking the substrate for degradation or functional modification[1][3][5][7]. This interface confers substrate specificity in the ubiquitination pathway, playing a central role in cellular protein turnover, signal transduction, cell cycle, and stress responses. Current drug discovery efforts, notably PROTAC and molecular glue technologies, focus on modulating this interface to induce selective degradation of disease-related proteins, presenting new opportunities and challenges in drug development[4][6][8].

Other names
E3 ligase–substrate interfaceE3–substrate binding surface
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Mechanism of action

Induced ubiquitination and degradation of specific target proteins through recruitment to E3 ligases - Inhibition or modulation of E3–substrate recognition (blocking protein degradation pathways)

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Biological functions

Protein ubiquitinationProtein degradation (via the ubiquitin-proteasome system)Signal transductionCell cycle regulationDNA repairImmune responseCell trafficking
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Disease associations

Cancer (e.g., MDM2-p53 interface, Parkin mutations)Neurodegenerative diseases (e.g., Parkin in Parkinson’s disease)InflammationInfectionMetabolic disorders
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Safety considerations

Off-target degradation of non-disease proteinsCellular toxicity due to widespread protein degradationPotential for resistance via mutations at the E3–substrate interfaceImbalance in cellular protein homeostasis
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Interacting drugs

PROTACs and related molecular glues (these are not traditional drugs but bifunctional molecules that recruit an E3 ligase to a target protein for forced degradation)

1 more in the full profile.

07

Biomarkers

Substrate protein levels (e.g., p53 for MDM2, androgen receptor for PROTACs)E3 ligase expression levels (e.g., cereblon, VHL, Parkin)Ubiquitination status of substrate proteins

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