Small-Molecule Inhibitors Allosterically Control Bruton's Tyrosine Kinase Assembly on the Membrane
- 1Colorado State University
Abstract
Bruton's tyrosine kinase (Btk) is the target of small-molecule, active site inhibitors for treatment of lymphomas and leukemias. Beyond its catalytic activity, Btk participates in signaling assemblies through scaffolding functions that can contribute to drug resistance. Here, we show that Btk forms micron-scale assemblies on membranes and that this behavior is allosterically controlled by ligand binding at the active site. Using supported lipid bilayers and total internal reflection fluorescence microscopy, we find that nucleotides and inhibitors including ibrutinib, acalabrutinib, and dasatinib promote assembly, whereas fenebrutinib and pirtobrutinib prevent assembly. Membrane organization is independent of catalysis but correlates with ligand-dependent changes in Btk conformational flexibility measured by hydrogen-deuterium exchange. These results reveal a previously unrecognized connection between active-site ligand binding and mesoscale membrane organization, demonstrating that kinase inhibitors can control Btk behavior beyond suppression of catalytic activity.
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BibTeX
@misc{fenton2026smallmolecule,
title = {{Small-Molecule Inhibitors Allosterically Control Bruton's Tyrosine Kinase Assembly on the Membrane}},
author = {A. D. Fenton and K. Todd and S. Shree and D. Y.-w. Lin and A. H. Andreotti and J. K. Chung},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.08.757093},
url = {https://www.biorxiv.org/content/10.64898/2026.10.08.757093v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Small-Molecule Inhibitors Allosterically Control Bruton's Tyrosine Kinase Assembly on the Membrane
AU - A. D. Fenton
AU - K. Todd
AU - S. Shree
AU - D. Y.-w. Lin
AU - A. H. Andreotti
AU - J. K. Chung
PY - 2026
DA - 2026/10/08
PB - bioRxiv
DO - 10.64898/2026.10.08.757093
UR - https://www.biorxiv.org/content/10.64898/2026.10.08.757093v1
AB - Bruton's tyrosine kinase (Btk) is the target of small-molecule, active site inhibitors for treatment of lymphomas and leukemias. Beyond its catalytic activity, Btk participates in signaling assemblies through scaffolding functions that can contribute to drug resistance. Here, we show that Btk forms micron-scale assemblies on membranes and that this behavior is allosterically controlled by ligand binding at the active site. Using supported lipid bilayers and total internal reflection fluorescence microscopy, we find that nucleotides and inhibitors including ibrutinib, acalabrutinib, and dasatinib promote assembly, whereas fenebrutinib and pirtobrutinib prevent assembly. Membrane organization is independent of catalysis but correlates with ligand-dependent changes in Btk conformational flexibility measured by hydrogen-deuterium exchange. These results reveal a previously unrecognized connection between active-site ligand binding and mesoscale membrane organization, demonstrating that kinase inhibitors can control Btk behavior beyond suppression of catalytic activity.
ER -