ArticleJournal of molecular biology2017
Selective Targeting of SH2 Domain-Phosphotyrosine Interactions of Src Family Tyrosine Kinases with Monobodies.
Article in Journal of molecular biology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 39 citations in OpenAlex.
- DYT8 drives lung adenocarcinoma through EGFR-mediated PSMC6 recruitment and uncharacterized phosphorylation at Ser 306 and 525 of c-Src.Acta pharmacologica Sinica · 2026Article
- Zebrafish frk Gene Knockout Shows Social Impairments Relevant to Autism and Delays Brain Development by Increasing Cell Proliferation.Autism research : official journal of the International Society for Autism Research · 2026Article
- Development of mirror-image monobodies targeting the oncogenic BCR::ABL1 kinase.Nature communications · 2024Article
- Cytosolic delivery of monobodies using the bacterial type III secretion system inhibits oncogenic BCR: ABL1 signaling.Cell communication and signaling : CCS · 2024Article
- Improving the pharmacokinetics, biodistribution and plasma stability of monobodies.Frontiers in pharmacology · 2024Article
- SOCS1 and SOCS3 as key checkpoint molecules in the immune responses associated to skin inflammation and malignant transformation.Frontiers in immunology · 2024Review
- Fyn nanoclustering requires switching to an open conformation and is enhanced by FTLD-Tau biomolecular condensates.Molecular psychiatry · 2023Article
- SOCS-JAK-STAT inhibitors and SOCS mimetics as treatment options for autoimmune uveitis, psoriasis, lupus, and autoimmune encephalitis.Frontiers in immunology · 2023Review
- Synthesis of the l- and d-SH2 domain of the leukaemia oncogene Bcr-Abl.RSC chemical biology · 2022Article
- Engineering Binders with Exceptional Selectivity.Methods in molecular biology (Clifton, N.J.) · 2022Article
- Tuning SAS-6 architecture with monobodies impairs distinct steps of centriole assembly.Nature communications · 2021Article
- Conformational interconversion of MLKL and disengagement from RIPK3 precede cell death by necroptosis.Nature communications · 2021Article
- SOCS Proteins in Immunity, Inflammatory Diseases, and Immune-Related Cancer.Frontiers in medicine · 2021Review
- Heparanase, cell signaling, and viral infections.Cellular and molecular life sciences : CMLS · 2020Review
- Modular transient nanoclustering of activated β2-adrenergic receptors revealed by single-molecule tracking of conformation-specific nanobodies.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Selective inhibition of STAT3 signaling using monobodies targeting the coiled-coil and N-terminal domains.Nature communications · 2020Article
- Btk SH2-kinase interface is critical for allosteric kinase activation and its targeting inhibits B-cell neoplasms.Nature communications · 2020Article
- Review
- Monobodies as enabling tools for structural and mechanistic biology.Current opinion in structural biology · 2020Review
- Targeted Protein Degradation through Cytosolic Delivery of Monobody Binders Using Bacterial Toxins.ACS chemical biology · 2019Article
Corrections and comments
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Authors and funding
9 authors at 4 institutions in 2 countries.
Funding
Abstract
The binding of Src-homology 2 (SH2) domains to phosphotyrosine (pY) sites is critical for the autoinhibition and substrate recognition of the eight Src family kinases (SFKs). The high sequence conservation of the 120 human SH2 domains poses a significant challenge to selectively perturb the interactions of even the SFK SH2 family against the rest of the SH2 domains. We have developed synthetic binding proteins, termed monobodies, for six of the SFK SH2 domains with nanomolar affinity. Most of these monobodies competed with pY ligand binding and showed strong selectivity for either the SrcA (Yes, Src, Fyn, Fgr) or SrcB subgroup (Lck, Lyn, Blk, Hck). Interactome analysis of intracellularly expressed monobodies revealed that they bind SFKs but no other SH2-containing proteins. Three crystal structures of monobody-SH2 complexes unveiled different and only partly overlapping binding modes, which rationalized the observed selectivity and enabled structure-based mutagenesis to modulate inhibition mode and selectivity. In line with the critical roles of SFK SH2 domains in kinase autoinhibition and T-cell receptor signaling, monobodies binding the Src and Hck SH2 domains selectively activated respective recombinant kinases, whereas an Lck SH2-binding monobody inhibited proximal signaling events downstream of the T-cell receptor complex. Our results show that SFK SH2 domains can be targeted with unprecedented potency and selectivity using monobodies. They are excellent tools for dissecting SFK functions in normal development and signaling and to interfere with aberrant SFK signaling networks in cancer cells.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.