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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

In-solution structural studies involving a phospholipase A 2-like myotoxin and a natural inhibitor: Plasticity of oligomeric assembly affects mechanisms of inhibition

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Author(s):
Cardoso, Fabio F. [1] ; de Souza, Maximilia F. [2] ; Oliveira, Cristiano L. P. [2] ; Fontes, Marcos R. M. [1]
Total Authors: 4
Affiliation:
[1] Univ Estadual Paulista, UNESP, Inst Biociencias, Dept Biofis & Farmacol, Rua Prof Doutor Antonio Celso Wagner Zanin 250, Botucatu, SP - Brazil
[2] Univ Sao Paulo, Inst Fis, Rua Matao 1371, Sao Paulo, SP - Brazil
Total Affiliations: 2
Document type: Journal article
Source: Biochimie; v. 181, p. 145-153, FEB 2021.
Web of Science Citations: 0
Abstract

Snakebite envenomation has been categorized by World Health Organization as a category A neglected tropical disease, since it causes chronic psychological disorders, physical disablement and death. Ophidian accidents may cause local myonecrosis that cause drastic sequelae, which are not efficiently neutralized via serum therapy. Phospholipase A(2)-like (PLA(2)-like) myotoxins have a major role in the local effects caused by several snake venoms. We previously demonstrated that chicoric acid (CA) is an efficient inhibitor of the BthTX-I myotoxin and solved the X-ray structure of complex. Herein, we assess the oligomeric behavior of the BthTX-I/CA complex in solution under different physical-chemical conditions and using toxin obtained by two different biochemical methodologies to fully elucidate structural bases of inhibition of myotoxins by CA. We demonstrated the ability of PLA(2)-like proteins to form different oligomeric assemblies in the presence of certain inhibitors, which can also be modulated by buffer polarity change. In the presence of ethanol, BthTX-I/CA remains predominantly in a monomeric conformation, which prevents it from being in its active form (dimeric conformation). In contrast, in the absence of ethanol, the tetramer assembly was observed, which hid key regions of the protein responsible for docking and disruption of the muscle membrane. Therefore, the ``plasticity{''} of these proteins with regard to their abilities to form oligomeric assemblies is a key issue for the future development of therapeutic agents to complement of serum therapy. (C) 2020 Elsevier B.V. and Societe Francaise de Biochimie et Biologie Moleculaire (SFBBM). All rights reserved. (AU)

FAPESP's process: 15/17286-0 - Structural and functional studies aiming to understand the role of snake venoms toxins and how to inhibit their biological activity
Grantee:Marcos Roberto de Mattos Fontes
Support Opportunities: Regular Research Grants
FAPESP's process: 12/07112-6 - Structural and functional studies with Bothropstoxin-I, from Bothrops jararacussu snake venom, and caffeic acid derivates
Grantee:Fábio Florença Cardoso
Support Opportunities: Scholarships in Brazil - Doctorate
FAPESP's process: 18/16092-5 - Investigating colloidal systems by scattering methods
Grantee:Cristiano Luis Pinto de Oliveira
Support Opportunities: Regular Research Grants