Structure of dystrophia myotonica protein kinase.

Journal article

Dystrophia myotonica protein kinase (DMPK) is a serine/threonine kinase composed of a kinase domain and a coiled-coil domain involved in the multimerization. The crystal structure of the kinase domain of DMPK bound to the inhibitor bisindolylmaleimide VIII (BIM-8) 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 coiled-coil domains are required for stable dimer formation. The kinase domain is in an active conformation, with a fully-ordered and correctly positioned alphaC helix, and catalytic residues in a conformation competent for catalysis. The conserved hydrophobic motif at the C-terminal extension of the kinase domain is bound to the N-terminal lobe of the kinase domain, despite being unphosphorylated. Differences in the arrangement of the C-terminal extension compared to the closely related Rho-associated 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 BIM-8 inhibitor occupies the ATP site and has similar binding mode as observed in PDK1.

Authors: Elkins, J; Amos, A; Niesen, F; Pike, A; Fedorov, O

• Publication status: Published
• Journal: Protein science : a publication of the Protein Society
• Volume: 18
• Issue: 4
• Pages: 782-791
• Publication date: 2009-04-01
• DOI: 10.1002/pro.82
• EISSN: 1469-896X
• ISSN: 0961-8368
• Language: English
• Keywords: Protein Binding; Protein Multimerization; Protein Interaction Domains and Motifs; Crystallography, X-Ray; Humans; Amino Acid Sequence; Molecular Sequence Data; Indoles; Protein-Serine-Threonine Kinases; Animals; Protein Conformation; Maleimides