Excitable cells and tissues like muscle or brain show a
highly fluctuating consumption of ATP, which is efficiently
regenerated from a large pool of phosphocreatine by the
enzyme creatine kinase (CK). The enzyme exists in tissue—as
well as compartment-specific isoforms. Numerous pathologies
are related to the CK system: CK is found to be overexpressed
in a wide range of solid tumors, whereas functional impairment
of CK leads to a deterioration in energy metabolism, which
is phenotypic for many neurodegenerative and age-related
diseases. The crystal structure of chicken cytosolic brain-type
creatine kinase (BB-CK) has been solved to 1.41 Å
resolution by molecular replacement. It represents the
most accurately determined structure in the family of guanidino
kinases. Except for the N-terminal region (2–12),
the structures of both monomers in the biological dimer
are very similar and closely resemble those of the other
known structures in the family. Specific Ca2+-mediated
interactions, found between two dimers in the asymmetric
unit, result in structurally independent heterodimers differing
in their N-terminal conformation and secondary structure.
The high-resolution structure of BB-CK presented in this
work will assist in designing new experiments to reveal
the molecular basis of the multiple isoform-specific properties
of CK, especially regarding different subcellular locations
and functional interactions with other proteins. The rather
similar fold shared by all known guanidino kinase structures
suggests a model for the transition state complex of BB-CK
analogous to the one of arginine kinase (AK). Accordingly,
we have modeled a putative conformation of CK in the transition
state that requires a rigid body movement of the entire
N-terminal domain by rms 4 Å from the structure without
substrates.