Calmodulin-ligand complexes

Calmodulin (CaM), a key player in intracellular Ca2+-signal transduction. It is a small protein containing two Ca2+-binding EF-hand motives in its both domains. We studied its complexes with small molecular ligands taking different effects on calmodulin action.

An extraordinarily high affinity arylalkylamine-type calmodulin antagonist competes for the hydrophobic pockets of CaM with target proteins or with the classical CaM antagonist, trifluoperazine (TFP). Its complex with CaM shows extended contacts burying large hydrophobic surfaces.

We solved the crystal structure of CaM complexed with a derivative of the anticancer drug vinblastine (KAR-2) and studied the complex in solution by NMR spectroscopy. In contrast to vinblastine KAR-2 does not have antagonistic effect on CaM-modulated processes, though they show similar CaM affinity. KAR-2 binds in a region of CaM overlapping only partially with the binding sites of the target proteins. That explains why KAR-2 does not prevent calmodulin from binding most of its physiological targets.

KAR-2 binding by calmodulin


Dr. Judit Ovádi, Ovádi group, Institute of Enzymology Budapest
Dr. Zsolt Böcskei, Chinoin Pharmaceuticals, Budapest

Structures determined

1A29, 1QIV, 1QIW, 1XA5, 3IF7

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