Abstract
Dystrophia myotonica protein kinase (DMPK) is a serine/threonine kinase composed of a kinase domain and a coiledโcoil domain involved in the multimerization. The crystal structure of the kinase domain of DMPK bound to the inhibitor bisindolylmaleimide VIII (BIMโ8) revealed a dimeric enzyme associated by a conserved dimerization domain. The affinity of dimerisation suggested that the kinase domain alone is insufficient for dimerisation in vivo and that the coiledโcoil domains are required for stable dimer formation. The kinase domain is in an active conformation, with a fullyโordered and correctly positioned ฮฑC helix, and catalytic residues in a conformation competent for catalysis. The conserved hydrophobic motif at the Cโterminal extension of the kinase domain is bound to the Nโterminal lobe of the kinase domain, despite being unphosphorylated. Differences in the arrangement of the Cโterminal extension compared to the closely related Rhoโassociated kinases include an altered PXXP motif, a different conformation and binding arrangement for the turn motif, and a different location for the conserved NFD motif. The BIMโ8 inhibitor occupies the ATP site and has similar binding mode as observed in PDK1.