Article
Biology
Pavel Pohl, Rohit Joshi, Olivia Petrvalska, Tomas Obsil, Veronika Obsilova
Summary: The study investigated the structural basis of Nedd4-2 regulation by 14-3-3 and identified phosphorylated Ser342 and Ser448 as key residues facilitating 14-3-3 binding. The Nedd4-2:14-3-3 complex induces a structural rearrangement of Nedd4-2 by inhibiting interactions between its structured domains.
COMMUNICATIONS BIOLOGY
(2021)
Article
Pharmacology & Pharmacy
Claire C. Munier, Christian Ottmann, Matthew W. D. Perry
Summary: The 14-3-3 proteins play crucial roles in regulating the inflammatory response at genetic, molecular, and cellular levels. They affect key components of the immune response and can lead to clinical syndromes when their recognition processes are disrupted. Abnormal levels of 14-3-3 contribute to undesirable immune responses and chronic inflammatory conditions.
PHARMACOLOGICAL RESEARCH
(2021)
Article
Multidisciplinary Sciences
Michael J. Roy, Minglyanna G. Surudoi, Ashleigh Kropp, Jianmei Hou, Weiwen Dai, Joshua M. Hardy, Lung-Yu Liang, Thomas R. Cotton, Bernhard C. Lechtenberg, Toby A. Dite, Xiuquan Ma, Roger J. Daly, Onisha Patel, Isabelle S. Lucet
Summary: PEAK pseudokinases regulate cell migration, invasion and proliferation by recruiting key signaling proteins to the cytoskeleton. The researchers elucidate the molecular details of key PEAK signaling interactions with the adapter proteins CrkII and Grb2 and the scaffold protein 14-3-3. They identify a conserved high affinity 14-3-3 motif on PEAK3 and demonstrate its role as a molecular switch to regulate CrkII binding and signaling via Grb2.
NATURE COMMUNICATIONS
(2023)
Article
Chemistry, Multidisciplinary
Bente A. Somsen, Fenna W. B. Craenmehr, Wei-Hong W. Liu, Auke A. Koops, Marloes A. M. Pennings, Emira J. Visser, Christian Ottmann, Peter J. Cossar, Luc Brunsveld
Summary: Molecular glues represent a novel approach in drug discovery, however, the targeted stabilization of protein complexes is still challenging due to a lack of drug design rules. This study demonstrates the successful development of a peptide-based molecular glue that selectively stabilizes the 14-3-3/ChREBP protein-protein interaction by utilizing the functional mapping of hotspots.
Article
Chemistry, Multidisciplinary
Stephen I. Ting, Dylan W. Snelson, Tucker R. Huffman, Akihiro Kuroo, Ryota Sato, Ryan A. Shenvi
Summary: Researchers have reported a concise synthesis of (-)-cotylenol via a 10-step asymmetric entry. This route features a reaction that tolerates steric hindrance and a tandem reaction that establishes an 8-membered ring. The method sets the stage for focused library synthesis.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Multidisciplinary Sciences
Loes M. Stevers, Madita Wolter, Graeme W. Carlile, Dwight Macdonald, Luc Richard, Frank Gielkens, John W. Hanrahan, David Y. Thomas, Sai Kumar Chakka, Mark L. Peterson, Helmut Thomas, Luc Brunsveld, Christian Ottmann
Summary: This study identified a macrocycle compound that stabilizes the interaction between mutant CFTR and the chaperone-like protein 14-3-3, rescuing its biological function.
NATURE COMMUNICATIONS
(2022)
Article
Biochemistry & Molecular Biology
Nanami Ogino, Ryoma Masuda, Louvy Lynn Punzalan, Emi Yamashita, Shota Igaue, Yoshihisa Inoue, Junko Ohkanda
Summary: In this study, a series of FC derivatives were synthesized and their stabilization effects on the binding of 14-3-3 to phosphopeptides were evaluated. The results showed that introducing an amino group at a specific position on the glucoside moiety improves stabilization. Furthermore, 6' amino benzyl 21b exhibited higher antiproliferative activity.
BIOORGANIC & MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Multidisciplinary
Peter J. Cossar, Madita Wolter, Lars van Dijck, Dario Valenti, Laura M. Levy, Christian Ottmann, Luc Brunsveld
Summary: The study emphasizes the importance of considering the selectivity of stabilizer molecules in addition to their potency. Targeting the phosphorylated motifs on 14-3-3 hub proteins can lead to the stabilization of specific protein-protein interactions and drive selective PPI stabilization through cooperative complex formation.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2021)
Article
Biochemistry & Molecular Biology
Hendrik J. Brink, Rick Riemens, Stephanie Thee, Berend Beishuizen, Daniel da Costa Pereira, Maikel Wijtmans, Iwan de Esch, Martine J. Smit, Albertus H. de Boer
Summary: In this study, a fragment-based drug screening approach was used to identify a PPI stabilizer targeting 14-3-3. The stabilizer was found to cooperatively stabilize 14-3-3 and enhance its binding to client proteins. This finding provides a tool compound for investigating the interactions between 14-3-3 and client proteins.
Review
Biochemistry & Molecular Biology
Wan Gi Byun, Donghyun Lim, Seung Bum Park
Summary: This review discusses the potential of targeting PRIs using small molecules, the tools for observing PRIs in biochemical and cell-based experiments, and various PRI modulators. Emerging technologies and challenges in the development of PRI modulators are also highlighted.
CURRENT OPINION IN CHEMICAL BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Chang-Heng Hsieh, Chia-Cheng Chou, Ya-Ching Fang, Po-Hao Hsu, Yi-Hung Chiu, Chi-Sheng Yang, Guey-Mei Jow, Chih-Yung Tang, Chung-Jiuan Jeng
Summary: Endogenous 14-3-3 proteins play a chaperone-like role in regulating the stability of Eag1 protein and modulators of 14-3-3 have therapeutic potential in correcting protein expression of disease-causing Eag1 mutants.
CELL AND BIOSCIENCE
(2023)
Article
Chemistry, Multidisciplinary
Emira J. Visser, Priyadarshini Jaishankar, Eline Sijbesma, Marloes A. M. Pennings, Edmee M. F. Vandenboorn, Xavier Guillory, R. Jeffrey Neitz, John Morrow, Shubhankar Dutta, Adam R. Renslo, Luc Brunsveld, Michelle R. Arkin, Christian Ottmann
Summary: Small-molecule stabilization of protein-protein interactions (PPIs) is a promising strategy in chemical biology and drug discovery. In this study, a fragment-linking approach targeting the interface of 14-3-3 and a peptide derived from the estrogen receptor alpha (ERα) protein was developed. The initial hybrid molecule, supported by 20 crystal structures, was optimized to selectively stabilize the 14-3-3/ERα interaction by 25-fold. The high-resolution structures of the fragments, co-crystals, and linked fragments demonstrate a feasible strategy for developing orthosteric PPI stabilizers.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Biology
Mengyao Gao, Lingling Zhao, Zitong Zhang, Junjie Wang, Chunyu Wang
Summary: In this study, a stacking ensemble computational framework, SELPPI, was developed based on a genetic algorithm and tree-based machine learning method to predict new modulators targeting protein-protein interactions. Various basic learners and chemical descriptors were used for primary predictions, and the most efficient method was selected as the meta learner. The model outperformed all existing models on the pdCSM-PPI datasets.
COMPUTERS IN BIOLOGY AND MEDICINE
(2023)
Review
Biochemistry & Molecular Biology
Veronika Obsilova, Tomas Obsil
Summary: Signal transduction cascades efficiently transmit chemical and/or physical signals from the extracellular environment to intracellular compartments, thereby eliciting an appropriate cellular response. 14-3-3 proteins, as a family of highly conserved scaffolding molecules, play a crucial role in modulating the function of other proteins primarily through phosphorylation-dependent mechanisms. They participate in key cellular processes such as cell-cycle control, apoptosis, signal transduction, energy metabolism, and protein trafficking. However, our understanding of the molecular mechanisms by which 14-3-3 proteins regulate their binding partners remains insufficient, despite intensive research into their protein-protein interactions. This review article aims to provide an overview of recent structural studies of 14-3-3 protein complexes in order to further explore the regulatory mechanisms of these proteins.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Hetao Chen, Hang Zhang, Pu Chen, Song Xiang
Summary: This study elucidated the interaction mechanism between CRTCs and 14-3-3, as well as their crucial roles in nuclear translocation and activation of gene transcription. The discovery of a novel salt bridge structure expanded the understanding of this interaction.
JOURNAL OF MOLECULAR BIOLOGY
(2021)
Article
Oncology
Esther Visser, Sylvia A. A. M. Genet, Remco P. P. A. de Kock, Ben E. E. M. van den Borne, Maggy Youssef-El Soud, Huub N. A. Belderbos, Gerben Stege, Marleen E. A. de Saegher, Susan C. Van't Westeinde, Luc Brunsveld, Maarten A. C. Broeren, Daan Van de Kerkhof, Birgit A. L. M. Deiman, Federica Eduati, Volkher Scharnhorst
Summary: This study aimed to evaluate the performance of liquid biopsy-based decision-support algorithms in diagnosing lung cancer and subtyping it into small-cell and non-small-cell lung cancer. The study found that using protein tumor markers and circulating tumor DNA could improve the accuracy of lung cancer diagnosis. These algorithms are particularly important for patients who cannot undergo tissue biopsies or have inconclusive results.
Article
Biochemistry & Molecular Biology
Nick H. J. Geertjens, Pim J. de Vink, Tim Wezeman, Albert J. Markvoort, Luc Brunsveld
Summary: Mathematical modelling is essential for understanding complex phenomena in chemistry and biology. This study presents a framework for equilibrium models that can be applied to molecular glues and other multicomponent systems. The framework simplifies the analysis and understanding of biomolecular systems, reducing the time and expertise required to integrate equilibrium models into research and development.
RSC CHEMICAL BIOLOGY
(2023)
Article
Chemistry, Multidisciplinary
Thijs W. van Veldhuisen, Wiggert J. Altenburg, Madelief A. M. Verwiel, Lenne J. M. Lemmens, Alexander F. Mason, Maarten Merkx, Luc Brunsveld, Jan C. M. van Hest
Summary: Membraneless organelles play a crucial role in spatial organization and regulation of intracellular processes. This study presents a coacervate system that utilizes the 14-3-3 scaffold protein to investigate enzymatically regulated recruitment of 14-3-3-binding proteins. Synthetic coacervates efficiently load 14-3-3 and phosphorylated binding partners, allowing for increased local concentration and controlled release of proteins.
ADVANCED MATERIALS
(2023)
Article
Biochemistry & Molecular Biology
Alessia Lasorsa, Krishnendu Bera, Idir Malki, Elian Dupre, Francois-Xavier Cantrelle, Hamida Merzougui, Davy Sinnaeve, Xavier Hanoulle, Jozef Hritz, Isabelle Landrieu
Summary: Phosphorylation of Tau protein is associated with Alzheimer's disease progression, and the interaction between Tau and BIN1 is modulated by phosphorylation. Nuclear magnetic resonance spectroscopy studies show that phosphorylation affects the local structure and dynamics of Tau peptide, which in turn affects the binding with BIN1.
Article
Biochemical Research Methods
Sylvia A. A. M. Genet, Jur R. E. Wolfs, Chris B. A. K. Vu, Madita Wolter, Maarten A. C. Broeren, Joost van Dongen, Luc Brunsveld, Volkher Scharnhorst, Daan Van de Kerkhof
Summary: We developed a multiplex immunoaffinity liquid chromatography-tandem mass spectrometry (IA LC-MS/MS) assay for quantification of neuron-specific enolase (NSE) alpha and NSE gamma in human serum. The assay showed good accuracy and precision, and measured substantially lower total NSE concentrations compared to conventional immunoassay.
JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES
(2023)
Article
Chemistry, Multidisciplinary
Bente A. Somsen, Rick J. C. Schellekens, Carlo J. A. Verhoef, Michelle R. Arkin, Christian Ottmann, Peter J. Cossar, Luc Brunsveld
Summary: A new approach called "molecular locks" was developed to rapidly access molecular glue-like tool compounds by reversibly reacting with a nucleophilic amino acid on partner proteins. This approach selectively and potently stabilizes protein complexes for supporting molecular glue drug discovery.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Chemistry, Multidisciplinary
Dyana N. Kenanova, Emira J. Visser, Johanna M. Virta, Eline Sijbesma, Federica Centorrino, Holly R. Vickery, Mengqi Zhong, R. Jeffrey Neitz, Luc Brunsveld, Christian Ottmann, Michelle R. Arkin
Summary: Dysregulation of protein-protein interactions (PPIs) commonly leads to disease. PPI stabilization has recently been explored for drug discovery, and disulfide tethering is a method for identifying small molecules that can selectively target PPIs. In this study, disulfide tethering was used to discover selective PPI stabilizers for the hub protein 14-3-3 sigma. Screening of complexes between 14-3-3 and phosphopeptides derived from client proteins identified stabilizing fragments and revealed the ability of some peptides to interact with the tethered fragments. The study validated several fragment stabilizers and provided diverse structures for future optimization.
ACS CENTRAL SCIENCE
(2023)
Article
Chemistry, Multidisciplinary
Emira J. Visser, Priyadarshini Jaishankar, Eline Sijbesma, Marloes A. M. Pennings, Edmee M. F. Vandenboorn, Xavier Guillory, R. Jeffrey Neitz, John Morrow, Shubhankar Dutta, Adam R. Renslo, Luc Brunsveld, Michelle R. Arkin, Christian Ottmann
Summary: Small-molecule stabilization of protein-protein interactions (PPIs) is a promising strategy in chemical biology and drug discovery. In this study, a fragment-linking approach targeting the interface of 14-3-3 and a peptide derived from the estrogen receptor alpha (ERα) protein was developed. The initial hybrid molecule, supported by 20 crystal structures, was optimized to selectively stabilize the 14-3-3/ERα interaction by 25-fold. The high-resolution structures of the fragments, co-crystals, and linked fragments demonstrate a feasible strategy for developing orthosteric PPI stabilizers.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Biochemistry & Molecular Biology
Qi Wu, Federica Centorrino, Xavier Guillory, Madita Wolter, Christian Ottmann, Peter J. Cossar, Luc Brunsveld
Summary: Protein-protein interaction modulation is a promising approach in drug discovery. This study discovered a new PPI stabilizer and revealed its mechanism of action through structure-activity relationship and X-ray structural analysis.
Article
Chemistry, Multidisciplinary
Markella Konstantinidou, Emira J. Visser, Edmee Vandenboorn, Sheng Chen, Priyadarshini Jaishankar, Maurits Overmans, Shubhankar Dutta, R. Jeffrey Neitz, Adam R. Renslo, Christian Ottmann, Luc Brunsveld, Michelle R. Arkin
Summary: The stabilization of protein-protein interactions (PPIs) is a promising strategy in chemical biology and drug discovery. This study presents the structure-based optimization of a nonselective fragment to develop selective and highly potent small-molecule stabilizers. Through determination of the binding modes of 37 compounds and optimization of the stabilizer's structure, potency and selectivity similar to a natural product were achieved.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Biochemistry & Molecular Biology
Blaz Andlovic, Geronimo Heilmann, Sabrina Ninck, Sebastian A. Andrei, Federica Centorrino, Yusuke Higuchi, Nobuo Kato, Luc Brunsveld, Michelle Arkin, Sascha Menninger, Axel Choidas, Alexander Wolf, Bert Klebl, Farnusch Kaschani, Markus Kaiser, Jan Eickhoff, Christian Ottmann
Summary: The study reveals that the natural product family of fusicoccanes (FCs) exhibits anti-cancer activity, particularly when combined with established therapeutic agents, by stabilizing 14-3-3 protein-protein interactions (PPIs). Through proteomics analysis, specific 14-3-3 PPIs induced by interferon a (IFNa) and stabilized by FCs in OVCAR-3 cells were identified. Biophysical and structural biology studies further confirm these 14-3-3 PPIs as physical targets of FC stabilization, and transcriptome analysis suggests possible mechanisms for the synergistic effect of IFNa/FC treatment on cancer cells.
CELL CHEMICAL BIOLOGY
(2023)
Article
Chemistry, Multidisciplinary
Carlo J. A. Verhoef, Danielle F. F. Kay, Lars van Dijck, Richard G. G. Doveston, Luc Brunsveld, Aneika C. C. Leney, Peter J. J. Cossar
Summary: This study investigates the mechanisms of covalent molecular glue stabilization by combining native mass spectrometry (MS) with biophysical and structural techniques. The study elucidates the stoichiometry, assembly order, and contributions of covalent and non-covalent binding events in a multi-component protein-ligand complex. The findings provide insights into covalent small molecule ligation mechanisms and inform the development of molecular glues.
Article
Chemistry, Multidisciplinary
Markella Konstantinidou, Emira J. Visser, Edmee Vandenboorn, Sheng Chen, Priyadarshini Jaishankar, Maurits Overmans, Shubhankar Dutta, R. Jeffrey Neitz, Adam R. Renslo, Christian Ottmann, Luc Brunsveld, Michelle R. Arkin
Summary: The stabilization of protein-protein interactions (PPIs) is a promising strategy in chemical biology and drug discovery. In this study, selective and potent small-molecule stabilizers for the 14-3-3s/ERa complex were optimized through structure-based optimization. By targeting specific amino acids and locking the conformation, the optimized covalent stabilizer achieved potency, cooperativity, and selectivity similar to a natural product. The study highlights the value of addressing structure, kinetics, and cooperativity in molecular glue development.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
