The immediate purpose of the proposed research is to understand the chemical details that underlie the action of presynaptic neurotoxins from snake venom. the long range goal is to use this detailed structural information to probe the characteristic and unique features of the presynaptic membrane and the mechanism of the neurosecretory process. Presynaptic neurotoxins from venom belong to a much larger homologous family of enzymes called phospholipase A2. These enzymes hydrolyze the 2-acyl ester link of glycerol phospholipids if and only if the phospholipids are in membranes or membrane-like lamellar aggregates. The structure/function relationships of this novel class of enzymes are under study in our lab and elsewhere. The phospholipasic neurotoxins are classical phospholipases A2, but have the remarkable additional to ignore the abundance of membrane surface en route to their target. Once at the presynaptic membrane of the neuromuscular junction they become active locally and hydrolytically disrupt neurosecretory activity. We intend to establish the molecular events in the neighborhood of the presynaptic membrane that activates these toxins. Through high resolution crystallography of the toxins and their appropriate complexes we will establish the molecular details of these highly specific interactions that are characteristic of and unique to the target membrane and its environment. Whereas it may be difficult, if not impossible, to visualize directly the molecular structure of the reactive elements of the presynaptic surface, the complementary surface of the toxin can be established in atomic detail by crystallographic methods and thus provides a well-defined molecular template with which to probe the structure and function of the presynaptic membrane.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
7R01NS025867-02
Application #
3411371
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1988-03-01
Project End
1993-02-28
Budget Start
1989-09-25
Budget End
1990-02-28
Support Year
2
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Yale University
Department
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520