Structure of dystrophia myotonica protein kinase |
| Jonathan M. Elkins 1 *, Ann Amos 1, Frank H. Niesen 1, Ashley C.W. Pike 1, Oleg Fedorov 1, Stefan Knapp 1 2 * |
| 1Structural Genomics Consortium, Nuffield Department of Medicine, Oxford University, Old Road Campus Research Building, Oxford, OX3 7DQ, United Kingdom 2Department of Clinical Pharmacology, Oxford University, Old Road Campus Research Building, Oxford, OX3 7DQ, United Kingdom |
| email: Jonathan M. Elkins (jon.elkins@sgc.ox.ac.uk) Stefan Knapp (stefan.knapp@sgc.ox.ac.uk) |
*Correspondence to Jonathan M. Elkins, Structural Genomics Consortium, Oxford University, Old Road Campus Research Building, Old Road Campus, Roosevelt Drive, Oxford, OX3 7DQ, UK
*Correspondence to Stefan Knapp, Structural Genomics Consortium, Oxford University, Old Road Campus Research Building, Old Road Campus, Roosevelt Drive, Oxford, OX3 7DQ, UK
Funded by:
Canadian Institutes for Health Research Canadian Foundation for Innovation Genome Canada (Ontario Genomics Institute) GlaxoSmithKline Karolinska Institutet Knut and Alice Wallenberg Foundation Ontario Innovation Trust Ontario Ministry for Research and Innovation Merck & Co., Inc. Novartis Research Foundation Swedish Agency for Innovation Systems Swedish Foundation for Strategic Research Wellcome Trust
| Keywords |
| kinase myotonic dystrophy crystallization DMPK bisindolylmaleimide BIM enzymes active sites structure crystallography protein crystallization enzyme inhibitors protein structures |
| Abstract |
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  C 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. |
Received: 23 September 2008; Revised: 19 December 2008; Accepted: 29 December 2008
| Digital Object Identifier (DOI) |
10.1002/pro.82 About DOI
