HOMO AND HETERODIMERIC SNAKE VENOM PHOSPHOLIPASE A2S: STRUCTURE AND INHIBITION

CHRISTIAN BETZEL1, TEJ P. SINGH2, R.K. ARNI3,4 AND NICOLAY GENOV5

1Department of Biochemistry and Molecularbiology, University of Hamburg, c/o DESY, Notkestrasse 85, 22603 Hamburg, Germany

2Department of Biophysics, All India Institute of Medical Sciences, New Delhi 110029, India

3Department of Physics, IBILCE/UNESP, SJRP, Brazil & 4Center for Applied Toxinology, CAT-CEPID, São Paulo, SP, Brazil.

4Institute of Organic Chemistry, Bulgarian Academy of Sciences, “Akad. G. Bonchev”-str. bl. 9, Sofia 1113, Bulgaria

Phospholipases A2 (PLA2s) play an important role in a number of physiological processes such as phospholipid metabolism and remodelling, mediator production, homeostasis of cellular membranes, host defense and signal transduction. In the same time, they are involved in a number of inflammatory diseases. Snake venom PLA2s exert additionally a wide variety of pharmacological activities and for all these reasons it is of high pharmacological and medical interest to develop specific inhibitors, which can be used for a rational design of anti-inflammatory drugs. We have determined the three-dimensional structures of a number of homo- and heterodimeric, snake venom PLA2s, native as well as in complex with naturally occurring anti-inflammatory agents and synthetic inhibitors to high resolution, applying synchrotron radiation The structures revealed specific interactions that are important for the molecular recognition and this knowledge was applied for de novo design of inhibitors with improved potency.

Acknowledgements. Financially supported by CAPES/DAAD