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Structural basis of PROTAC cooperative recognition for selective protein degradation

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Structural basis of PROTAC cooperative recognition for selective protein degradation. / Gadd, Morgan S; Testa, Andrea; Lucas, Xavier; Chan, Kwok-Ho; Chen, Wenzhang; Lamont, Douglas J; Zengerle, Michael; Ciulli, Alessio.

In: Nature Chemical Biology, Vol. 13, No. 5, 31.05.2017, p. 514-521.

Research output: Contribution to journalJournal article

Harvard

Gadd, MS, Testa, A, Lucas, X, Chan, K-H, Chen, W, Lamont, DJ, Zengerle, M & Ciulli, A 2017, 'Structural basis of PROTAC cooperative recognition for selective protein degradation', Nature Chemical Biology, vol. 13, no. 5, pp. 514-521. https://doi.org/10.1038/nchembio.2329

APA

Gadd, M. S., Testa, A., Lucas, X., Chan, K-H., Chen, W., Lamont, D. J., Zengerle, M., & Ciulli, A. (2017). Structural basis of PROTAC cooperative recognition for selective protein degradation. Nature Chemical Biology, 13(5), 514-521. https://doi.org/10.1038/nchembio.2329

Vancouver

Gadd MS, Testa A, Lucas X, Chan K-H, Chen W, Lamont DJ et al. Structural basis of PROTAC cooperative recognition for selective protein degradation. Nature Chemical Biology. 2017 May 31;13(5):514-521. https://doi.org/10.1038/nchembio.2329

Author

Gadd, Morgan S ; Testa, Andrea ; Lucas, Xavier ; Chan, Kwok-Ho ; Chen, Wenzhang ; Lamont, Douglas J ; Zengerle, Michael ; Ciulli, Alessio. / Structural basis of PROTAC cooperative recognition for selective protein degradation. In: Nature Chemical Biology. 2017 ; Vol. 13, No. 5. pp. 514-521.

Bibtex

@article{a1d166d6ee2a4f7b95124a4062472e9a,
title = "Structural basis of PROTAC cooperative recognition for selective protein degradation",
abstract = "Inducing macromolecular interactions with small molecules to activate cellular signaling is a challenging goal. PROTACs (proteolysis-targeting chimeras) are bifunctional molecules that recruit a target protein in proximity to an E3 ubiquitin ligase to trigger protein degradation. Structural elucidation of the key ternary ligase-PROTAC-target species and its impact on target degradation selectivity remain elusive. We solved the crystal structure of Brd4 degrader MZ1 in complex with human VHL and the Brd4 bromodomain (Brd4BD2). The ligand folds into itself to allow formation of specific intermolecular interactions in the ternary complex. Isothermal titration calorimetry studies, supported by surface mutagenesis and proximity assays, are consistent with pronounced cooperative formation of ternary complexes with Brd4BD2. Structure-based-designed compound AT1 exhibits highly selective depletion of Brd4 in cells. Our results elucidate how PROTAC-induced de novo contacts dictate preferential recruitment of a target protein into a stable and cooperative complex with an E3 ligase for selective degradation.",
keywords = "Amino Acid Sequence, Crystallography, X-Ray, Dipeptides, Elongin, Heterocyclic Compounds, 3-Ring, Humans, Models, Molecular, Multiprotein Complexes, Nuclear Proteins, Protein Binding, Protein Conformation, Proteolysis, Small Molecule Libraries, Structure-Activity Relationship, Thermodynamics, Transcription Factors, Ubiquitin-Protein Ligases, Von Hippel-Lindau Tumor Suppressor Protein",
author = "Gadd, {Morgan S} and Andrea Testa and Xavier Lucas and Kwok-Ho Chan and Wenzhang Chen and Lamont, {Douglas J} and Michael Zengerle and Alessio Ciulli",
year = "2017",
month = may
day = "31",
doi = "10.1038/nchembio.2329",
language = "English",
volume = "13",
pages = "514--521",
journal = "Nature Chemical Biology",
issn = "1552-4450",
publisher = "Nature Publishing Group",
number = "5",

}

RIS

TY - JOUR

T1 - Structural basis of PROTAC cooperative recognition for selective protein degradation

AU - Gadd, Morgan S

AU - Testa, Andrea

AU - Lucas, Xavier

AU - Chan, Kwok-Ho

AU - Chen, Wenzhang

AU - Lamont, Douglas J

AU - Zengerle, Michael

AU - Ciulli, Alessio

PY - 2017/5/31

Y1 - 2017/5/31

N2 - Inducing macromolecular interactions with small molecules to activate cellular signaling is a challenging goal. PROTACs (proteolysis-targeting chimeras) are bifunctional molecules that recruit a target protein in proximity to an E3 ubiquitin ligase to trigger protein degradation. Structural elucidation of the key ternary ligase-PROTAC-target species and its impact on target degradation selectivity remain elusive. We solved the crystal structure of Brd4 degrader MZ1 in complex with human VHL and the Brd4 bromodomain (Brd4BD2). The ligand folds into itself to allow formation of specific intermolecular interactions in the ternary complex. Isothermal titration calorimetry studies, supported by surface mutagenesis and proximity assays, are consistent with pronounced cooperative formation of ternary complexes with Brd4BD2. Structure-based-designed compound AT1 exhibits highly selective depletion of Brd4 in cells. Our results elucidate how PROTAC-induced de novo contacts dictate preferential recruitment of a target protein into a stable and cooperative complex with an E3 ligase for selective degradation.

AB - Inducing macromolecular interactions with small molecules to activate cellular signaling is a challenging goal. PROTACs (proteolysis-targeting chimeras) are bifunctional molecules that recruit a target protein in proximity to an E3 ubiquitin ligase to trigger protein degradation. Structural elucidation of the key ternary ligase-PROTAC-target species and its impact on target degradation selectivity remain elusive. We solved the crystal structure of Brd4 degrader MZ1 in complex with human VHL and the Brd4 bromodomain (Brd4BD2). The ligand folds into itself to allow formation of specific intermolecular interactions in the ternary complex. Isothermal titration calorimetry studies, supported by surface mutagenesis and proximity assays, are consistent with pronounced cooperative formation of ternary complexes with Brd4BD2. Structure-based-designed compound AT1 exhibits highly selective depletion of Brd4 in cells. Our results elucidate how PROTAC-induced de novo contacts dictate preferential recruitment of a target protein into a stable and cooperative complex with an E3 ligase for selective degradation.

KW - Amino Acid Sequence

KW - Crystallography, X-Ray

KW - Dipeptides

KW - Elongin

KW - Heterocyclic Compounds, 3-Ring

KW - Humans

KW - Models, Molecular

KW - Multiprotein Complexes

KW - Nuclear Proteins

KW - Protein Binding

KW - Protein Conformation

KW - Proteolysis

KW - Small Molecule Libraries

KW - Structure-Activity Relationship

KW - Thermodynamics

KW - Transcription Factors

KW - Ubiquitin-Protein Ligases

KW - Von Hippel-Lindau Tumor Suppressor Protein

U2 - 10.1038/nchembio.2329

DO - 10.1038/nchembio.2329

M3 - Journal article

C2 - 28288108

VL - 13

SP - 514

EP - 521

JO - Nature Chemical Biology

JF - Nature Chemical Biology

SN - 1552-4450

IS - 5

ER -