DMPK1

DMPK1

DMPK1: Human myotonin-protein kinase, Form I
PDB Code: 2VD5
Description
DMPK is a Ser/Thr kinase of the AGC group of protein kinases. This kinase is expressed in skeletal muscle at neuromuscular junctions, myotendinous junctions, terminal cisternae of the sarcoplasmic reticulum (SR), intercalated discs in the cardiac muscle as well as in liver.
DMPK is activated in response to G protein second messengers but in contrast to other members of this family no GTPase binding domain has been described. When expressed it is maintained in an inactive conformation by an auto-regulatory C-terminal coiled-coil region.
DMPK is critical to the modulation of cardiac contractility and to the maintenance of proper cardiac conduction. It also plays a role in muscle differentiation by controlling the rearrangement of the cytoskeleton that takes place during elongation and fusion of myblasts into myotubes.
Low DMPK activity has been associated to the development of myotonic dystrophy (DM, Steinert disease), a neurodegenerative disorder characterized by myotonia, muscle wasting in the distal extremities, cataract, hypogonadism, defective endocrine functions and cardiac arrhythmias. Low DMPK expression levels in diseased tissue are the result of an amplified trinucleotide CTG repeat in the 3-prime untranslated region. Unaffected individuals have between 5 and 37 copies whereas DM patients who are minimally affected have at least 50 repeats, while more severely affected patients have expansion of the repeat-containing segment up to several kilobases. The CTG repeats are thought to alter local chromatin structure resulting in hyperstable nucleosomes that inhibit the passage of transcription complexes.
Here we present the structure of the kinase domain of DMPK in complex with the bisindoyl maleide inhibitor BIM VIII.

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