ArticleNature communications2020
Btk SH2-kinase interface is critical for allosteric kinase activation and its targeting inhibits B-cell neoplasms.
Article in Nature communications, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers, 1 of them a synthesis that pooled it.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
22 citing papers in PubMed, 1 synthesis or guideline pooled it, 44 citations in OpenAlex.
- Bruton's Tyrosine Kinase (BTK) Inhibitors and Autoimmune Diseases: Making Sense of BTK Inhibitor Specificity Profiles and Recent Clinical Trial Successes and Failures.Frontiers in immunology · 2021Pooled it
- Docirbrutinib is a pan-mutant BTK inhibitor and inhibits B-cell receptor signaling in chronic lymphocytic leukemia cells in preclinical and early clinical investigations.Blood cancer journal · 2026Trial
- Targeting of kinases to treat neurodegenerative diseases.Pharmacological reviews · 2026Review
- Mechanism of activation of an ancestral TEC kinase by PIPNpj structural biology · 2026Article
- Article
- Update on Structure and Function of SH2 Domains: Mechanisms and Emerging Targeting Strategies.International journal of molecular sciences · 2025Review
- Covalent and Non-Covalent BTK Inhibition in Chronic Lymphocytic Leukemia Treatment.Current treatment options in oncology · 2025Review
- Article
- BTK inhibitors and next-generation BTK-targeted therapeutics for B-cell malignancies.Archives of pharmacal research · 2025Review
- Case report: A panorama gene profile of ovarian cancer metastasized to axillary lymph node.Frontiers in immunology · 2025Article
- Article
- AlphaFold-predicted protein structures and small-angle X-ray scattering: insights from an extended examination of selected data in the Small-Angle Scattering Biological Data Bank.Journal of applied crystallography · 2023Article
- Allosteric regulation and inhibition of protein kinases.Biochemical Society transactions · 2023Review
- A phospho-harmonic orchestra plays the NLRP3 score.Frontiers in immunology · 2023Review
- SH2 Domains: Folding, Binding and Therapeutical Approaches.International journal of molecular sciences · 2022Review
- Synthetic Reprogramming of Kinases Expands Cellular Activities of Proteins.Angewandte Chemie (International ed. in English) · 2022Article
- Alchemical Free Energy Calculations to Investigate Protein-Protein Interactions: the Case of the CDC42/PAK1 Complex.Journal of chemical information and modeling · 2022Article
- Review
- BTK operates a phospho-tyrosine switch to regulate NLRP3 inflammasome activity.The Journal of experimental medicine · 2021Article
- Review
Corrections and comments
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Authors and funding
15 authors at 5 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Bruton's tyrosine kinase (Btk) is critical for B-cell maturation and activation. Btk loss-of-function mutations cause human X-linked agammaglobulinemia (XLA). In contrast, Btk signaling sustains growth of several B-cell neoplasms which may be treated with tyrosine kinase inhibitors (TKIs). Here, we uncovered the structural mechanism by which certain XLA mutations in the SH2 domain strongly perturb Btk activation. Using a combination of molecular dynamics (MD) simulations and small-angle X-ray scattering (SAXS), we discovered an allosteric interface between the SH2 and kinase domain required for Btk activation and to which multiple XLA mutations map. As allosteric interactions provide unique targeting opportunities, we developed an engineered repebody protein binding to the SH2 domain and able to disrupt the SH2-kinase interaction. The repebody prevents activation of wild-type and TKI-resistant Btk, inhibiting Btk-dependent signaling and proliferation of malignant B-cells. Therefore, the SH2-kinase interface is critical for Btk activation and a targetable site for allosteric inhibition.
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What OpenQuestion holds
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.