COMPLEXES OF CALMODULIN WITH ANTAGONISTS. Zs. Bcskei, V. Harmat, D. Menyhrd, G. Nray-Szab, Etvs University of Sciences, Budapest, Hungary, B. Vrtessy, J. Ovdi, Institute of Enzimology of the Hungarian Academy of Sciences, Budapest, Hungary

Calmodulin is believed to be the most imprtant mediator of Ca^2+-dependent signaling in eucarytic cells and is thought to play an essetial role in processes like cell proliferation and growth. Calmodulin is therefore a target for certain drugs and consequently a target of drug design experiments.

The structures of calmodulin as well as its complexes with a number of substrates has received widespread attention recently. This is because calmodulin plays a regulatory role in a number of processes by transforming the value of the intracellular Ca²⁺ -ion concetration into a more structured information. If Ca²⁺ concentration increases than two hydrophobic binding pockets of calmodulin become exposed facilitating the binding of certain amphilphilic regulatory helices of at least 30 different proteins of high biological importance. Calmodulin mediated enzyme activation can be efficiently inhibited by a number of pharmacological agents (antipsychotics, antidepressants, muscle relaxants etc.). Crystal structure of TFP (a potent antipsychotic phenothiazine type drug, kind of a reference molecule on the area) with calmodulin is known from the literature¹. This shows that due to the effect of the small molecular antagonist TFP, calmoduline undergoes a very similar conformational change to that it suffers when it binds regulatory oligopeptide pieces of proteins normally regulated by calmodulin.

We have recently shown that drugs fairly different form TFP result in very similar calmodulin conformational changes. Furthermore we have also demonstrated that at low, physiologically relevant TFP concentrations the binding of the second TFP occurs in the C-terminal domain of calmodulin, unlike it was proposed earlier. A quaterner complex of calmoduline with Ca²⁺ and two different type of drugs has also been investigated resulting in some new insights into the inactivation of calmodulin.

¹ Vandonselaar, M., Hickie, R.A., Quail, J.W., Delbaere, L.T.J. (1994) Nature Structural Biology 1 795-801.