2VD5

Structure of Human Myotonic Dystrophy Protein Kinase in Complex with the Bisindoylmaleide inhibitor BIM VIII

Summary for 2VD5

• Entry DOI: 10.2210/pdb2vd5/pdb
• Descriptor: DMPK PROTEIN, 3-[1-(3-AMINOPROPYL)-1H-INDOL-3-YL]-4-(1-METHYL-1H-INDOL-3-YL)-1H-PYRROLE-2,5-DIONE (3 entities in total)
• Functional Keywords: serine/threonine-protein kinase, kinase, transferase, atp-binding, nucleotide-binding, cardiac contractility, muscle differentiation
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 2
• Total formula weight: 93007.64

Authors

Pike, A.C.W.,Amos, A.,Elkins, J.,Bullock, A.,Guo, K.,Fedorov, O.,Bunkoczi, G.,Filippakopoulos, P.,Pilka, E.S.,Ugochukwu, E.,Umeano, C.,Niesen, F.,Sundstrom, M.,Weigelt, J.,Edwards, A.,Arrowsmith, C.H.,von Delft, F.,Knapp, S. (deposition date: 2007-09-30, release date: 2007-11-06, Last modification date: 2024-11-06)

Primary citation

Elkins, J.,Amos, A.,Niesen, F.,Pike, A.C.W.,Fedorov, O.,Knapp, S.
Structure of Dystrophia Myotonica Protein Kinase.
Protein Sci., 18:782-, 2009

PubMed 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 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.

PubMed: 19309729
DOI: 10.1002/PRO.82

Experimental method

X-RAY DIFFRACTION (2.8 Å)