Modeling the CRL4A ligase complex to predict target protein ubiquitination induced by cereblon-recruiting PROTACs

Bai, Nan; Riching, Kristin M.; Makaju, Aman; Wu, Hao; Acker, Timothy M.; Ou, Shuching; Zhang, Yaru; Shen, Xiaomeng; Bulloch, Daryl; Rui, Huan; Gibson, Bradford W.; Daniels, Danette L.; Urh, Marjeta; Rock, Brooke M.; Humphreys, Sara C.

doi:10.1016/j.jbc.2022.101653

Cited by 43 publications

(49 citation statements)

References 55 publications

(66 reference statements)

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“…Recent studies have demonstrated the utility of computational modelling approaches to simulate degradation kinetics from a mechanistic model of ternary complex and ubiquitination reaction kinetics 45 or predict successful ubiquitination through modelling of ternary complex conformational dynamics. [72][73][74][75] These conformational models include molecular dynamics simulations and ternary complex docking and ensemble clustering that either take advantage of available structures for protein: ligand complexes or incorporate biophysical techniques such as HDX-MS to inform on protein:protein interfaces. [72][73][74][75] Many of these methods have resulted in accurate alignment of ternary ensembles with solved x-ray crystal structures.…”

Section: Ubiquitinationmentioning

confidence: 99%

The importance of cellular degradation kinetics for understanding mechanisms in targeted protein degradation

et al. 2022

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Section: Ubiquitinationmentioning

confidence: 99%

The importance of cellular degradation kinetics for understanding mechanisms in targeted protein degradation

et al. 2022

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“…8a). The target in the ternary complexes of different HBF molecules may have different ubiquitination rates because of the difference in their structural ensembles, 27,28 which affects the exposure of lysines on the target surface to ubiquitination. 29 If ubiquitination is fast, a transient ternary complex is sufficient for ubiquitination to take place, and fast dissociation of the ternary complex-corresponding to a low cooperativity-leads to both high turnover of the HBF molecules and rapid production of free, polyubiquitinated target ready for degradation; in contrast, high cooperativity-and thus a very stable ternary complex-may hinder the catalytic turnover and slow down the degradation.…”

Section: The Effect Of Cooperativity On Degradationmentioning

confidence: 99%

Modeling the effect of cooperativity in ternary complex formation and targeted protein degradation mediated by heterobifunctional degraders

Park

Izaguirre

Coffey

et al. 2022

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Chemically induced proximity between certain endogenous enzymes and a protein of interest (POI) inside cells may cause post-translational modifications to the POI with biological consequences and potential therapeutic effects. Heterobifunctional (HBF) molecules that bind with one functional part to a target POI and with the other to an E3 ligase induce the formation of a target-HBF-E3 ternary complex, which can lead to ubiquitination and proteasomal degradation of the POI. Targeted protein degradation (TPD) by HBFs offers a promising approach to modulating disease-associated proteins, especially those that are intractable using other therapeutic approaches, such as enzymatic inhibition. The three-way interactions among the HBF, the target POI, and the ligase—including the protein-protein interaction (PPI) between the POI and the ligase—contribute to the stability of the ternary complex, manifested as positive or negative binding cooperativity in its formation. How such cooperativity affects HBF-mediated degradation is an open question. In this work, we develop a pharmacodynamic model that describes the kinetics of the key reactions in the TPD process, and we use this model to investigate the role of cooperativity in the ternary complex formation and in the target POI degradation. Our model predicts that there is an optimal range of cooperativity values for efficient degradation, which depends on the kinetic rates of the other steps in the process. We also develop a statistical inference model for determining cooperativity in intracellular ternary complex formation from cellular assay data, and demonstrate it by quantifying the change in cooperativity due to site-directed mutagenesis at the POI-ligase interface of the SMARCA2-ACBI1-VHL ternary complex. Our pharmacodynamic model provides a quantitative framework to dissect the complex HBF-mediated TPD process and may inform the rational design of effective HBF degraders.

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“…Targeted protein degradation is an emerging therapeutic modality which, instead of inhibiting the activity of a drug target, acts by inducing degradation of the target protein itself [1, 2]. It employs so-called monofunctional degraders such as molecular glues or heterobifunctional degraders such as Proteolysis Targeting Chimeras (PROTACs) which act as proximity-inducing compounds.…”

Section: Introductionmentioning

confidence: 99%

“…Results of the BOTCP method for ternary complex prediction on unbound structures before the refinement 1. The best rank containing at least one model with DockQ≥0.23 2. The total number of clusters 3.…”

mentioning

confidence: 99%

Bayesian Optimization for Ternary Complex Prediction (BOTCP)

Rao¹,

Tunjic²,

Brunsteiner³

et al. 2022

Preprint

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Proximity-inducing compounds (PICs) are an emergent drug technology through which a protein of interest (POI), often a drug target, is brought into the vicinity of a second protein which modifies the POI's function, abundance or localisation, giving rise to a therapeutic effect. One of the best-known examples for such compounds are heterobifunctional molecules known as proteolysis targeting chimeras (PROTACs). PROTACs reduce the abundance of the target protein by establishing proximity to an E3 ligase which targets the protein towards degradation via the ubiquitin-proteasomal pathway. Design of PROTACs in silico requires the computational prediction of the ternary complex consisting of POI, PROTAC molecule, and the E3 ligase. Here, we present a novel machine learning-based method for predicting PROTAC-mediated ternary complex structures using Bayesian optimization. We show how a fitness score combining an estimation of protein-protein interactions with PROTAC binding energy calculations enables the sample-efficient exploration of candidate structures. Furthermore, our method presents two novel scores for filtering and reranking which take PROTAC stability (Autodock-Vina based PROTAC stability score) and protein interaction restraints (the TCP-AIR score) into account. We evaluate our method using DockQ scores and demonstrate, that even with a clustering that require members to have a high similarity, i.e. with smaller clusters, we can assign high ranks to those clusters that contain poses close to the experimentally determined native structure of the ternary complexes. We also demonstrate the resultant improved yeild of near-native poses in these clusters.

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Modeling the CRL4A ligase complex to predict target protein ubiquitination induced by cereblon-recruiting PROTACs

Cited by 43 publications

References 55 publications

The importance of cellular degradation kinetics for understanding mechanisms in targeted protein degradation

The importance of cellular degradation kinetics for understanding mechanisms in targeted protein degradation

Modeling the effect of cooperativity in ternary complex formation and targeted protein degradation mediated by heterobifunctional degraders

Bayesian Optimization for Ternary Complex Prediction (BOTCP)

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