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 (PDB codes):

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

Kapcsolódó publikációk

  • István Horváth , Veronika Harmat , András Perczel , Villő Pálfi , László Nyitray , Attila Nagy , Emma Hlavanda , Gábor Náray-Szabó , Judit Ovádi
    The structure of the complex of calmodulin with KAR-2: a novel mode of binding explains the unique pharmacology of the drug
    J. Biol. Chem. 280(9):8266-8274. | PMID: 15596444 (2005) Kivonat
  • Veronika Harmat , Zsolt Böcskei , Gábor Náray-Szabó , Imre Bata , Andrea S. Csutor , István Hermecz , Péter Arányi , Beáta Szabó , Károly Liliom , Beáta G. Vértessy
    A new potent calmodulin antagonist with arylalkylamine structure: crystallographic, spectroscopic and functional studies
    J. Mol. Biol. 297(3):747-755. | DOI: 10.1006/jmbi.2000.3607 | PMID: 10731425 (2000) Kivonat
  • Erika Kovács , Veronika Harmat , Judit Tóth , Beáta G. Vértessy , Károly Módos , József Kardos , Károly Liliom
    Structure and mechanism of calmodulin binding to a signaling sphingolipid reveal new aspects of lipid-protein interactions
    FASEB J. 24(10):3829-39. | DOI: 10.1096/fj.10-155614 | PMID: 20522785 (2010) Kivonat