Btk SH2-kinase interface is critical for allosteric kinase activation and its targeting inhibits B-cell neoplasms

Daniel P. Duarte, Allan J. Lamontanara, Giuseppina Sala, Sukyo Jeong, Yoo-Kyoung Sohn, Alejandro Panjkovich, Sandrine Georgeon, Tim Kükenshöner, Maria J. Marcaida, Florence Pojer, Marco Vivo, Dmitri Svergun, Hak-Sung Kim, Matteo Dal Peraro and Oliver Hantschel ()
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Daniel P. Duarte: School of Life Sciences, École polytechnique fédérale de Lausanne (EPFL
Allan J. Lamontanara: School of Life Sciences, École polytechnique fédérale de Lausanne (EPFL
Giuseppina Sala: Istituto Italiano di Tecnologia, Via Morego 30
Sukyo Jeong: Korea Advanced Institute of Science and Technology (KAIST)
Yoo-Kyoung Sohn: Korea Advanced Institute of Science and Technology (KAIST)
Alejandro Panjkovich: Hamburg Unit
Sandrine Georgeon: School of Life Sciences, École polytechnique fédérale de Lausanne (EPFL
Tim Kükenshöner: School of Life Sciences, École polytechnique fédérale de Lausanne (EPFL
Maria J. Marcaida: École polytechnique fédérale de Lausanne (EPFL)
Florence Pojer: École polytechnique fédérale de Lausanne (EPFL)
Marco Vivo: Istituto Italiano di Tecnologia, Via Morego 30
Dmitri Svergun: Hamburg Unit
Hak-Sung Kim: Korea Advanced Institute of Science and Technology (KAIST)
Matteo Dal Peraro: École polytechnique fédérale de Lausanne (EPFL)
Oliver Hantschel: School of Life Sciences, École polytechnique fédérale de Lausanne (EPFL

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-16128-5

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