Protein–protein interfaces in molecular glue-induced ternary complexes: classification, characterization, and prediction

Rui, Huan; Ashton, Kate; Min, Jaeki; Wang, Connie; Potts, Patrick Ryan

doi:10.1039/d2cb00207h

Cited by 25 publications

(14 citation statements)

References 197 publications

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“…We identified intrinsic affinities between BRD4 and either of the two E3 ligases even in the absence of ligands. This reinforces the emerging concept that molecular glue degraders often stabilize pre-existing, albeit functionally inconsequential E3-target interactions 43,47,48 and further suggests that these affinities may be essential for degradation via intramolecular glue degraders. The exclusive requirement of IBG1 and IBG4 on DCAF16 and DCAF11, respectively, suggests that the varying warhead arrangement and linker architecture align the BRD4 bromodomains in different orientations relative to each other, generating distinct protein-ligand surfaces that are selectively recognized by the two ligases.…”

Section: Discussionsupporting

confidence: 79%

Targeted protein degradation via intramolecular bivalent glues

Hsia

Hinterndorfer

Cowan

et al. 2023

Preprint

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Targeted protein degradation is a drug modality represented by compounds that recruit a target to an E3 ubiquitin ligase to promote target ubiquitination and proteasomal degradation. Historically, the field distinguishes monovalent degraders from bifunctional degraders (PROTACs) that connect target and ligase via separate binding ligands joined via a linker1-4. Here, we elucidate the mechanism of action of a PROTAC-like degrader of the transcriptional coactivator BRD4, composed of a BRD4 ligand linked to a ligand for the E3 ligase CRL4DCAF15. Using orthogonal CRISPR/Cas9 screens we identify the degrader activity is independent of DCAF15, and relies on a different CRL4 substrate receptor, DCAF16. We demonstrate an intrinsic affinity between BRD4 and DCAF16, which is dependent on the tandem bromodomains of BRD4 and further increased by the degrader without physically engaging DCAF16 in isolation. Structural characterization of the resulting ternary complex reveals both BRD4 bromodomains are bivalently engaged in cis by the degrader and are bound to DCAF16 through several interfacial BRD4-DCAF16 and degrader-DCAF16 contacts. Our findings demonstrate that intramolecularly bridging domains can confer glue-type stabilization of intrinsic target-E3 interactions, and we propose this as a general strategy to modulate the surface topology of target proteins to nucleate co-opting of E3 ligases or other cellular effector proteins for effective proximity-based pharmacology.

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Section: Discussionsupporting

confidence: 79%

Targeted protein degradation via intramolecular bivalent glues

Hsia

Hinterndorfer

Cowan

et al. 2023

Preprint

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“…In contrast, MGs typically form ternary complexes by a defined order. [13] For example, the MG may display affinity for one of the proteins involved, which alters the binding surface and promotes binding of the partner protein (e. g., FKBP12-Rapamycin-mTOR). [14] Several features are used to describe the formation and productivity of small molecule-induced ternary complexes.…”

Section: Characterization and Development Of Degraders: Principles Of...mentioning

confidence: 99%

“…A PROTAC molecule may first bind to either the E3 ligase or the POI before recruiting the other. In contrast, MGs typically form ternary complexes by a defined order [13] . For example, the MG may display affinity for one of the proteins involved, which alters the binding surface and promotes binding of the partner protein (e. g., FKBP12‐Rapamycin‐mTOR) [14] …”

Section: Introductionmentioning

confidence: 99%

Biophysical and Computational Approaches to Study Ternary Complexes: A ‘Cooperative Relationship’ to Rationalize Targeted Protein Degradation

2023

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Degraders have illustrated that compound-induced proximity to E3 ubiquitin ligases can prompt the ubiquitination and degradation of disease-relevant proteins. Hence, this pharmacology is becoming a promising alternative and complement to available therapeutic interventions (e. g., inhibitors). Degraders rely on protein binding instead of inhibition and, hence, they hold the promise to broaden the druggable proteome. Biophysical and structural biology approaches have been the cornerstone of understanding and rationalizing degraderinduced ternary complex formation. Computational models have now started to harness the experimental data from these approaches with the aim to identify and rationally help design new degraders. This review outlines the current experimental and computational strategies used to study ternary complex formation and degradation and highlights the importance of effective crosstalk between these approaches in the advancement of the targeted protein degradation (TPD) field. As our understanding of the molecular features that govern druginduced interactions grows, faster optimizations and superior therapeutic innovations for TPD and other proximity-inducing modalities are sure to follow.

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“…E3 ligases are a class of enzymes that are involved in ubiquitin-mediated protein degradation, and they play a critical role in many cellular processes, including cell cycle regulation, DNA repair, and apoptosis. Selective targeting of E3 ligases has emerged as a promising strategy for developing novel therapeutics for various diseases, including cancer . Thus, predicting the target binding selectivity for E3 ligases using molecular fingerprint analysis can be useful in designing focused libraries for screening campaigns.…”

Section: Introductionmentioning

confidence: 99%

Pharmacophore-Based Machine Learning Model To Predict Ligand Selectivity for E3 Ligase Binders

Karki,

Gadiya,

Gribbon

et al. 2023

ACS Omega

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E3 ligases are enzymes that play a critical role in ubiquitin-mediated protein degradation and are involved in various cellular processes. Pharmacophore analysis is a useful approach for predicting E3 ligase binding selectivity, which involves identifying key chemical features necessary for a ligand to interact with a specific protein target cavity. While pharmacophore analysis is not always sufficient to accurately predict ligand binding affinity, it can be a valuable tool for filtering and/or designing focused libraries for screening campaigns. In this study, we present a fast and an inexpensive approach using a pharmacophore fingerprinting scheme known as ErG, which is used in a multi-class machine learning classification model. This model can assign the correct E3 ligase binder to its known E3 ligase and predict the probability of each molecule to bind to different E3 ligases. Practical applications of this approach are demonstrated on commercial libraries such as Asinex for the rational design of E3 ligase binders. The scripts and data associated with this study can be found on GitHub at .

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Protein–protein interfaces in molecular glue-induced ternary complexes: classification, characterization, and prediction

Abstract: Molecular glues are a class of small molecules that stabilize the interactions between proteins. Naturally occurring molecular glues are present in many areas of biology where they serve as central...

Cited by 25 publications

References 197 publications

Targeted protein degradation via intramolecular bivalent glues

Targeted protein degradation via intramolecular bivalent glues

Biophysical and Computational Approaches to Study Ternary Complexes: A ‘Cooperative Relationship’ to Rationalize Targeted Protein Degradation

Pharmacophore-Based Machine Learning Model To Predict Ligand Selectivity for E3 Ligase Binders

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