Btk SH2-kinase interface is critical for allosteric kinase activation and its targeting inhibits B-cell neoplasms
Btk SH2-kinase interface is critical for allosteric kinase activation and its targeting inhibits B-cell neoplasms
ABSTRACT Bruton’s tyrosine kinase (Btk) is a key component for B-cell maturation and activation. Btk loss-of-function mutations cause human X-linked agammaglobulinemia (XLA). In contrast, constitutive Btk signaling drives several B-cell neoplasms, which may be treated with tyrosine kinase inhibitors (TKIs). Here, we uncovered the molecular mechanism by which a subset of XLA mutations in the SH2 domain strongly perturbs 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 to which multiple XLA mutations map and which is required for Btk activation. As allosteric interactions provide unique targeting opportunities, we developed an engineered repebody protein binding to the Btk SH2 domain and able to disrupt the SH2-kinase interaction. The repebody prevented activation of wild-type and TKI-resistant Btk, inhibited 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.
Duarte Daniel P.、Lamontanara Allan J.、Panjkovich Alejandro、K¨1kensh?ner Tim、Marcaida Maria J.、De Vivo Marco、Kim Hak-Sung、Pojer Florence、Jeong Sukyo、Sohn Yoo-Kyoung、Svergun Dmitri、Hantschel Oliver、La Sala Giuseppina、Dal Peraro Matteo、Georgeon Sandrine
Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, ¨|cole polytechnique f¨|d¨|rale de Lausanne (EPFL)Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, ¨|cole polytechnique f¨|d¨|rale de Lausanne (EPFL)European Molecular Biology Laboratory (EMBL)Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, ¨|cole polytechnique f¨|d¨|rale de Lausanne (EPFL)Institute of Bioengineering, ¨|cole polytechnique f¨|d¨|rale de Lausanne (EPFL)Laboratory of Molecular Modeling and Drug Discovery, Istituto Italiano di TecnologiaDepartment of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST)Protein Crystallography Core Facility, School of Life Sciences, ¨|cole polytechnique f¨|d¨|rale de Lausanne (EPFL)Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST)Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST)European Molecular Biology Laboratory (EMBL)Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, ¨|cole polytechnique f¨|d¨|rale de Lausanne (EPFL)||Institute of Physiological Chemistry, Faculty of Medicine, University of MarburgLaboratory of Molecular Modeling and Drug Discovery, Istituto Italiano di Tecnologia||Institute of Bioengineering, ¨|cole polytechnique f¨|d¨|rale de Lausanne (EPFL)Institute of Bioengineering, ¨|cole polytechnique f¨|d¨|rale de Lausanne (EPFL)Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, ¨|cole polytechnique f¨|d¨|rale de Lausanne (EPFL)
基础医学分子生物学肿瘤学
Duarte Daniel P.,Lamontanara Allan J.,Panjkovich Alejandro,K¨1kensh?ner Tim,Marcaida Maria J.,De Vivo Marco,Kim Hak-Sung,Pojer Florence,Jeong Sukyo,Sohn Yoo-Kyoung,Svergun Dmitri,Hantschel Oliver,La Sala Giuseppina,Dal Peraro Matteo,Georgeon Sandrine.Btk SH2-kinase interface is critical for allosteric kinase activation and its targeting inhibits B-cell neoplasms[EB/OL].(2025-03-28)[2025-05-21].https://www.biorxiv.org/content/10.1101/862276.点此复制
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