Alpha-kinases, a recently identified class of protein kinases, have no sequence homology to conventional protein kinases. They include elongation factor-2 kinase (EF-2K), Dictyostelium myosin heavy chain kinases (MHCKs A, B and C), channel-kinases (ChaK1, ChaK2) and others not yet fully characterized. It is hypothesized that unlike conventional protein kinases that recognize their substrates in extended conformation, alpha-kinases recognize alpha-helices. Consistent with this, EF-2K cannot recognize a peptide corresponding to the phosphorylation site in EF-2, probably because the peptide isn't helical. However, EF-2K can phosphorylate a peptide corresponding to the phosphorylation site in the alpha-helical coiled-coil region of myosin heavy chain, even though the sequence of this peptide is very different from the EF-2 phosphorylation site. The recently determined 3-D structure of ChaK1 shows the overall fold of alpha-kinases is surprisingly similar to conventional kinases, with the exception of the putative substrate binding site. Using the ChaK1 structure, we performed homology modeling of the MHCK-A catalytic domains, and modeled docking of its substrate. In the MHCK-A model, the conformation of the active site cleft has a size and shape that accommodates a double-stranded coiled-coil, with the phosphorylation site in the right position to accept the tertiary phosphate. There are many good contacts over a broad interface, including 6 salt-bridges and 20 hydrogen-bonds. We also performed a structural analysis of ChaK1 to help interpret interesting experimental results. For instance, ChaK1 is unable to utilize GTP as a substrate, and is not inhibited by staurosporin. We hypothesize that these substrate specificities are both caused by the presence of a charged residue within the adenine binding pocket. Since this residue is conserved in all alpha-kinases, we predict that all alpha-kinases will be unable to utilize GTP as a substrate, and will not be inhibited by staurosporin.