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

By Qi Wang, Yakov Pechersky, Shiori Sagawa, Albert C. Pan, David E. Shaw

Posted 18 Apr 2018
bioRxiv DOI: 10.1101/304097 (published DOI: 10.1073/pnas.1819301116)

Bruton's tyrosine kinase (Btk) is critical for B-cell proliferation and activation, and the development of Btk inhibitors is a vigorously pursued strategy for the treatment of various B-cell malignancies. A detailed mechanistic understanding of Btk activation has, however, been lacking. Here, inspired by a previous suggestion that Btk activation might depend on dimerization of its lipid-binding PH-TH module on the cell membrane, we performed long-timescale molecular dynamics simulations of membrane-bound PH-TH modules and observed that they dimerized into a single predominant conformation. We found that the phospholipid PIP3 stabilized the dimer allosterically by binding at multiple sites, and that the effects of PH-TH mutations on dimer stability were consistent with their known effects on Btk activity. Taken together, our simulation results strongly suggest that PIP3-mediated dimerization of Btk at the cell membrane is a critical step in Btk activation.

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