(
A) The Src-like module of Btk forms a domain-swapped dimer in the crystal lattice, with one molecule per asymmetric unit. The SH3 domain and the kinase domain are intact, but the SH2 domain forms a domain-swapped dimer with another molecule. (
B) Molecular details of the domain-swapped SH2 dimer in Btk and Grb2 (
Schiering et al., 2000). The SH2 domain opens up at a position within the β-sheet, so that helix αB of one polypeptide chain packs against the β-sheet of the other. (
C) Interactions between the SH2-kinase linker and the kinase domain. Leu 390 of the linker stabilizes the inactive conformation of the kinase domain by being sandwiched between residues Trp 421 and Tyr 461 in the kinase domain. (
D) The ‘electrostatic switch’ in the Btk kinase domain. The active conformation of the Btk kinase domain is modeled from the crystal structure of Lck (PDB: 3LCK) (
Yamaguchi and Hendrickson, 1996) using Modeller (
Eswar et al., 2006). Activation entails a shuffling of salt-bridge and polar hydrogen-bond partners.