Structure of dystrophia myotonica protein kinase.
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.
Elkins
Jonathan M
JM
Structural Genomics Consortium, Nuffield Department of Medicine, Oxford University, Old Road Campus Research Building, Oxford, OX3 7DQ, United Kingdom.
Amos
Ann
A
Niesen
Frank H
FH
Pike
Ashley C W
AC
Fedorov
Oleg
O
Knapp
Stefan
S
D000595:Amino Acid Sequence; D000818:Animals; D018360:Crystallography, X-Ray; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000378:metabolism; D008301:Maleimides / Q000737:chemistry* / Q000378:metabolism; D008969:Molecular Sequence Data; D065636:Myotonin-Protein Kinase; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000378:metabolism
C585517:DMPK protein, human; D007211:Indoles; D008301:Maleimides; D065636:Myotonin-Protein Kinase; D017346:Protein Serine-Threonine Kinases; C064755:Ro 31-7549