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. 2020 Nov 23;9:e60470. doi: 10.7554/eLife.60470

Figure 1. Domain organization of full-length Bruton’s tyrosine kinase (BTK) and Ibrutinib binding site.

Figure 1.

(a) The BTK fragments used in this study are shown with key residues indicated above each domain. PHTH, Pleckstrin homology-Tec homology domain; PRR, proline-rich region; SH3, Src homology three domain; SH2, Src homology two domain; L, SH2-kinase linker; FL, full-length; 32LKD, SH3-SH2-linker-kinase domain; and LKD, linker-kinase domain. (b) Domain arrangement of BTK full-length (FL) in the autoinhibited conformation (left) based on the crystal structure of the BTK SH3-SH2-kinase (32LKD) fragment (PDB ID: 4XI2) and solution data supporting an autoinhibitory interaction between the PHTH domain and the activation loop face of the kinase domain (Amatya et al., 2019; Devkota et al., 2017). The location of T316 in the SH2 domain is indicated with a black circle. The active LKD fragment is depicted on the right. (c) The thiol group of C481 in the BTK kinase domain forms a covalent bond with the α,β unsaturated ketone of Ibrutinib. (d) Crystal structure (PDB ID: 5P9J) of BTK kinase domain (gray cartoon) bound to Ibrutinib, represented in pink sticks. The kinase domain N- and C-lobes are labeled, the activation loop is purple, the αC-helix yellow, side chains of the Lys/Glu pair are shown in cyan, sidechains of W395, Y551, and C481 are shown in yellow spheres, and the regulatory spine (R-spine) residues are shown as blue sticks and transparent surface.