Structural and functional studies of a snake venom phospholipase A2-like protein complexed to an inhibitor from Tabernaemontana catharinensis

Autor(es)

Borges, Rafael J. ; Cardoso, Fabio F. ; de Carvalho, Cicilia ; de Marino, Ivan ; Pereira, Paulo S. ; Soares, Andreimar M. ; Dal-Pai-Silva, Maeli ; Uson, Isabel ; Fontes, Marcos R. M.

• Tipo de documento: Artigo Científico
• Fonte: Biochimie; v. 206, p. 11-pg., 2023-02-17.

Resumo

Snake envenomation is an ongoing global health problem and tropical neglected disease that afflicts millions of people each year. The only specific treatment, antivenom, has several limitations that affects its proper distribution to the victims and its efficacy against local effects, such as myonecrosis. The main responsible for this consequence are the phospholipases A2 (PLA2) and PLA2-like proteins, such as BthTX-I from Bothrops jararacussu. Folk medicine resorts to plants such as Tabernaemontana catharinensis to palliate these and other snakebite effects. Here, we evaluated the effect of its root bark extract and one of its isolated compounds, 12-methoxy-4-methyl-voachalotine (MMV), against the in vitro paralysis and muscle damage induced by BthTX-I. Secondary and quaternary structures of BthTX-I were not modified by the interaction with MMV. Instead, this compound interacted in an unprecedented way with the region inside the toxin hydrophobic channel and promoted a structural change in Val31, loop 58-71 and Membrane Disruption Site. Thus, we hypothesize that MMV inhibits PLA2-like proteins by preventing entrance of fatty acid into the hydrophobic channel. These data may explain the traditional use of T. catharinensis extract and confirm MMV as a promising candidate to complement antivenom or a structural guide to develop more effective inhibitors.(c) 2022 Elsevier B.V. and Societe Francaise de Biochimie et Biologie Moleculaire (SFBBM). All rights reserved. (AU)

• Processo FAPESP: 19/05958-4 - EMU concedido no processo 2013/24705-3: sistema de cromatografia líquido de alta pressão
• Beneficiário: Marcos Roberto de Mattos Fontes
• Modalidade de apoio: Auxílio à Pesquisa - Programa Equipamentos Multiusuários
• Processo FAPESP: 16/24191-8 - Desenvolvimento de métodos para elucidação de estruturas cristalográficas e estudos estruturais do mecanismo tóxico de fosfolipases A2 homólogas de veneno de serpente
• Beneficiário: Rafael Junqueira Borges
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 20/10143-7 - Ferramentas estruturais para compreender mecanismos estruturais funcionais-funcionais de toxinas e desenvolver inibidores específicos
• Beneficiário: Marcos Roberto de Mattos Fontes
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 21/01463-0 - Desenvolvimento de agente antiofídico original de amplo espectro funcional e de caráter interespecífico
• Beneficiário: Fábio Florença Cardoso
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado