A mechanism for localized dynamics-driven activation in Bruton's tyrosine kinase

Abstract

Bruton's tyrosine kinase (BTK) plays a vital role in mature B-cell proliferation, development and function. Its inhibitors have gradually been applied for the treatment of many B-cell malignancies. However, because of treatment-associated drug resistance or low efficacy, it is urgent to develop new inhibitors and/or improve the efficacy of current inhibitors, where finding the intrinsic activation mechanism becomes the key to solve this problem. Here, we used BTK T474M mutation as a resistance model for inhibitors to study the mechanism of BTK activation and drug resistance by free molecular dynamics simulations. The results showed that the increase of kinase activity of T474M mutation is coming from the conformation change of the activation ring and ATP binding sites located in BTK N-terminus region. Specifically, the Thr 474 mutation changed the structure of A-loop and stabilized the binding site of ATP, thus promoting the catalytic ability in the kinase domain. This localized dynamics-driven activation mechanism and resistance mechanism of BTK may provide new ideas for drug development in B-cell malignancies.

Force-Regulated Calcium Signaling of Lymphoid Cell RPMI 8226 Mediated by Integrin α4β7/MAdCAM-1 in Flow

“…The external force existing in the cellular microenvironment is crucial for the interaction of most biomacromolecules and cellular signal transduction [ 28 ]. Several mechanical techniques have been applied to investigate the effects of forces at the cellular and molecular levels, including parallel-plate flow chambers, atomic force microscopes, biomembrane force probes, and molecular dynamics simulations [ 29 , 30 , 31 , 32 , 33 ]. Using molecular dynamics simulations, the interaction of integrin α v β 3 with its RGD ligands in a force-dependent process was demonstrated [ 33 ].…”

Comparison of Intermolecular Interactions of Irreversible and Reversible Inhibitors with Bruton’s Tyrosine Kinase via Molecular Dynamics Simulations

“…Local conformational changes were quantified based on angles and distance between relevant atoms of the systems. The ATP binding site of the BTK kinase domain is composed of three motifs, including the DFG motif chelating Mg 2+ , P-loop binding the ATP phosphate, and the hinge region binding ATP adenosine [ 5 ]. A probe radius of 0.14 nm was used to calculate the solvent-accessible surface area (SASA) [ 49 ], which is used to evaluate the level of exposure of amino acids to the solvent.…”

“…The binding sites of ATP and magnesium ions are located between these lobes. The activation loop [ 5 ] (A-loop: Asp539-Phe559) connects the two lobes and regulates binding with downstream molecules. Phosphorylation of Tyr551 at the C-terminal end of the A-loop increases BTK’s activity by ten folds [ 6 , 7 ].…”