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Significance Bruton’s tyrosine kinase (Btk) activation on the cell membrane is critical for B cell proliferation and development, and Btk inhibition is a promising treatment for several hematologic cancers and autoimmune diseases. Here, we examine Btk activation using the results of long-timescale molecular dynamics simulations. In our simulations, Btk lipid-binding modules dimerized on the membrane in a single predominant conformation. We observed that the phospholipid PIP3 —in addition to its expected role of recruiting Btk to the membrane—allosterically mediated dimer formation and stability by binding at two novel sites. Our results provide strong evidence that PIP3 -mediated dimerization of Btk at the cell membrane is a critical step in Btk activation and suggest a potential approach to allosteric Btk inhibitor development.

Structural mechanism for Bruton’s tyrosine kinase activation at the cell membrane