Comparison of ligand binding and conformational stability of human calmodulin with its homolog from the malaria parasite Plasmodium falciparum.

Calmodulin (CaM), the key calcium sensor of eukaryotic cells regulating a great number of target proteins, belongs to the most conserved proteins. We compared function and properties of CaMs from two evolutionarily distant species, the human (Homo sapiens) representing vertebrates, and the malaria parasite Plasmodium falciparum (Pf). The biophysical characterization revealed higher stability of Pf CaM attributed to the more stable C-terminal domain in both Ca2+ free and saturated states. In vitro binding and functional assays demonstrated that human and Pf CaM exhibit similar biochemical features involving small molecule inhibitor binding and target enzyme activation as illustrated by comparable affinities differing only within a factor of three. It has been reported that CaM antagonists proved to be antimalarials, so Pf CaM could be a potential target to combat malaria parasites. Indeed, we observed that phenotypically active compounds from the Malaria Box could show inhibitory action on Pf CaM, among them the most potent exhibited comparable inhibition to known antagonists of vertebrate CaM. However, based on the minor binding differences in Pf CaM to human CaM, we conclude that CaM is an unsuited target for human intervention against malaria, due to the likely interference with the host protein.