1Department of Biophysics, P. J. Safarik University,
Jesenna 5, 041 54 Kosice, Slovak Republic (http://bioflab.upjs.sk)
2Department
of Physical Chemistry, Arrhenius Laboratory, Stockholm University, Sweden
3International Laser Centre, Ilkovicova 3, 812 19
Bratislava, Slovak Republic
Protein kinase C (PKC), a family of serine/threonine kinases, is intimately
involved in the regulation of a variety of cellular functions such as gene
expression, cellular growth and differentiation. PKC is regulated by two
distinct mechanisms: by binding 3 molecules of ATP which regulates the active
site and subcellular localization of the enzyme, and by second messengers
(Ca2+, diacylglycerol, phorbol esters) which promote PKC's membrane association
and result to pseudosubstrate exposure. Phorbol 12-myristate-13-acetate (PMA),
powerful tumor-promoting agent, binds to the Cys1 and Cys2 domain in PKC on
membrane surface with nanomolar binding affinity. Molecular modelling [1] was
used for the study of PMA+dipalmitoylphosphatidylcholine (DPPC) bilayer and
Cys2+PMA+DPPC bilayer complexes. Function of hydrophobic and hydrogen bond
interactions between PMA and Cys2 domainin is discussed. Comparison with
existing experimental data showed that obtained molecular model of Cys2 domain
with its activator PMA on membrane surface is consistent with existing X-ray
[2] and NMR [3] results.
References:
1. E. Lindahl, B. Hess & D. Van
der Spoel, J. Mol. Mod., 7 (2001) 306-317.
2. G. Zhang, M.
G. Kazanietz, P. M. Blumberg & J. H. Hurley, Cell, 81, (1995) 917-924
3. R. X. Xu, T. Pawelczyk, T.-H. Xia & S. C. Brown,
Biochemistry, 36 (1997) 10709-10717