Structural and functional studies of Crotoxin and its subunits, in native assemblies and complexed with potential inhibitors

• Grant number: 22/08286-0
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: September 01, 2022
• End date: August 31, 2023
• Field of knowledge: Biological Sciences - Biophysics - Molecular Biophysics
• Principal Investigator: Marcos Roberto de Mattos Fontes
• Grantee: Beatriz Silveira Augusto
• Host Institution: Instituto de Biociências (IBB). Universidade Estadual Paulista (UNESP). Campus de Botucatu. Botucatu , SP, Brazil

Abstract

Snakebites are a worldwide public health problem, considered by the World Health Organization as a neglected tropical disease, which may lead to permanent debilitating sequelae and, eventually, to death. In Brazil, the Crotalus snake genus (popularly known as rattlesnakes) promotes the highest fatality rate by snakebites. The toxic effects promoted by crotalic venom are due to the action exerted mainly by Crotoxin (CTX), which is the heterodimeric complex formed by the non-covalent interaction of its acidic (CA or Crotapotin) and basic (CB) subunits. This basic counterpart is a phospholipase A2 (PLA 2 ) with nonspecific action alone, but is directed to the neurotoxic activity by CA/Crotapotin. In this context, although we know the identity of four different isoforms of each subunit, there is only one structurally elucidated isoform of CTX. Theremaining 15 combinations of CA-CB may present relevant changes in their structures, which reflect the different levels of toxicity observed and, consequently, in different ways for efficient inhibition. Thus, we propose structural (primary, secondary, tertiary and quaternary) and functional (enzymatic) studies of such proteins in their native state and in the presence of their potential inhibitors, in search of a deeper understanding of the assembly configuration of these proteins, as well as in new ways to theirneutralization.